Heterocyclic Compounds and Methods For Their Use

ABSTRACT

The present invention relates to heterocyclic compounds useful for antagonizing angiotensin II Type 2 (AT 2 ) receptor. More particularly the invention relates to piperazine and diazepine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT 2  receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.

FIELDS OF THE INVENTION

The present invention relates generally to compounds that are useful inantagonizing the angiotensin II type 2 (AT₂) receptor. Moreparticularly, the invention relates to heterocyclic compounds of formula(I) and their use as AT₂ receptor antagonists. Pharmaceuticalcompositions comprising the compounds and their use in modulating theAT₂ receptor and therapies that require modulation of the AT₂ receptorare described.

BACKGROUND OF THE INVENTION

Although the AT₂ receptor has been known since the 1980s, much less isknown about its biological function than the angiotensin II type 1 (AT₁)receptor, which has been studied for its functional effects onvasoconstriction, aldosterone release and cardiovascular growth [Wexleret al., 1996]. However, more recently the AT₂ receptor has beenimplicated in the differentiation and regeneration of neuronal tissue[Steckelings et al., 2005; Chakrabarty et al., 2008], cell proliferationand angiogenesis [Clere et al., 2010] and maintenance of bone mass [Izuet al., 2009].

AT₂ receptor antagonists have also recently been associated with thetreatment of pain, particularly inflammatory pain [WO 2007/106938] andneuropathic pain [WO 2006/066361], two types of pain which are difficultto treat or relieve. Impaired nerve conduction velocity is alsoassociated with nerve damage and has been implicated in peripheralneuropathies, Carpel Tunnel Syndrome, ulnar neuropathy, Guillian-BarréSyndrome, fascioscapulohumeral muscular dystrophy and spinal discherneation. Impaired nerve conduction velocity can result in diminishedreflex responses and altered peripheral sensation such as parathesia andin some cases pain and AT₂ receptor antagonists have been shown torestore nerve conduction velocity [WO 2011/088504].

While there are effective therapies for treating nociceptive pain,inflammatory and neuropathic pain are often resistant to thesetherapies. In addition, current therapies of neuropathic pain,inflammatory pain, impaired nerve conduction velocity and other types ofpain that are difficult to treat, have serious side effects, forexample, cognitive changes, sedation, nausea and in the case of narcoticdrugs, tolerance and dependence. There is a need for further therapiesthat treat or prevent neuropathic pain, inflammatory pain, impairednerve conduction velocity and other painful conditions that arecurrently difficult to treat.

Cell proliferation and angiogenesis are important biological functionsin normal tissue. However, uncontrolled cell proliferation andangiogenesis can lead to tumors and other proliferative disorders. Whilethere are some effective chemotherapies available for tumors, manyresult in unpleasant side effects and/or have high toxicity for normalcells. Further therapies for reducing or preventing abnormal cellproliferation in a controlled manner are required and AT₂ receptorantagonists have been shown to have antiproliferative activity [Clere etal., 2010].

Osteoporosis is a significant problem in older populations, especiallyin post-menopausal women. Current therapies for osteoporosis rely oncalcium supplementation. However, the control of bone formation and boneresorption is complex and further therapies for improving bone mass arerequired and AT₂ receptor antagonists have been shown to increase bonemass [Izu et al., 2009].

The role of the AT₂ receptor in modulating neuronal outgrowth andassociated effects of AT₂ receptor antagonists on reducing neuronaloutgrowth, indicates that AT₂ receptor antagonists may be usefultherapeutics in diseases characterized by aberrant nerve regeneration[Chakrabarty et al., 2008].

The present invention is predicated in part on the discovery ofheterocyclic azetidine and pyrrolidine compounds that have AT₂ receptorantagonist activity.

SUMMARY OF THE INVENTION

In a first aspect of the present invention there is provided a compoundof formula (I):

wherein

X is —CHR⁴—, —CH₂CHR⁴— or —C(═O)—;

R¹ is —C(═O)CHR⁵R⁶, —C(═O)NR⁵R⁶, —C(═O)CH₂CHR⁵R⁶, —C(═O)CH═CR⁵R⁶,—C(═S)CHR⁵R⁶, —C(═S)NR⁵R⁶, —C(═S)CH₂CHR⁵R⁶, —C(═S)CH═CR⁵R⁶,—C(═NR⁷)CHR⁵R⁶, —C(═NR⁷)NR⁵R⁶, —C(═NR⁷)CH₂CHR⁵R⁶ or —C(═NR⁷)CH═CR⁵R⁶;R² is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)R⁸, —C(═O)NHR⁷,—SO₂N(R⁷)₂, —W-cycloalkyl, —W-cycloalkenyl, —W-aryl, —W-heterocyclyl,—W-heteroaryl, —W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl,—W—Z—Y-heterocyclyl or —W—Z—Y-heteroaryl;R³ is a carboxylic acid, —CH₂CO₂H, —C(═O)C(═O)OH, —CH₂OH, —C(═O)NH₂,—CH₂C(═O)NH₂, —CN, —CH₂CN, a carboxylic acid biostere or aCH₂-carboxylic acid bioisotere;R⁴ is hydrogen or together with R² forms a fused cycloalkyl,cycloalkenyl, aryl, heterocyclyl or heteroaryl ring optionallysubstituted with one or two substituents selected from —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —C₁₋₆alkyleneR⁹, —C₂₋₆alkenyleneR⁹,—C₂₋₆alkynyleneR⁹, —OC₀₋₆alkyleneR⁹, —OC₂₋₆alkenyleneR⁹,—OC₂₋₆alkynyleneR⁹, —C(═O)C₀₋₆alkyleneR⁹, —C(═O)C₂₋₆alkenyleneR⁹,—C(═O)C₂₋₆alkynyleneR⁹, —C(═O)OC₀₋₆alkyleneR⁹, —C(═O)OC₂₋₆alkenyleneR⁹,—C(═O)OC₂₋₆alkynyleneR⁹, —SO₂NHC₀₋₆alkyleneR⁹, —SO₂NHC₂₋₆alkenyleneR⁹,—SO₂NHC₂₋₆alkynyleneR⁹, —NHSO₂C₀₋₆alkyleneR⁹, —NHSO₂C₂₋₆alkenyleneR⁹,—NHSO₂C₂₋₆alkynyleneR⁹, —NH(═O)NHR¹⁰, —NHC(═O)OR¹⁰ or —CH(OH)CH(OH)R¹⁰;R⁵ and R⁶ are independently selected from hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —CH₂cycloalkyl, —CH₂cycloalkenyl, —CH₂aryl,—CH₂heterocyclyl and —CH₂heteroaryl; provided that both R⁵ and R⁶ arenot hydrogen;R⁷ is hydrogen, —C₁₋₆alkyl, aryl or —C₁₋₆alkylenearyl;R⁸ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl or —C₁₋₆alkylenearyl;R⁹ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl;R¹⁰ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl,aryl, heterocyclyl or heteroaryl;W is a covalent bond, —SO—, —SO₂— —C(═O)—, —C(═O)N(R⁷)—,—C₂₋₄alkenylene-, —C₂₋₄alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-,—C₄alkyleneQ-, —C₂₋₄alkenyleneQ- or —C₂₋₄alkynyleneQ-;Z is -cycloalkyl-, -cycloalkenyl-, -aryl-, -heterocyclyl- or-heteroaryl-;Y is a covalent bond, —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—,—N(R⁷)C(═O)—, —C(═O)N(R⁷)—, —C₁₋₃alkylene-, —C₂₋₃alkenylene-,—C₂₋₃alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-, -QC₁₋₄alkylene-,-QC₂₋₄alkenylene-, -QC₂₋₄alkynylene-, —C₁₋₄alkyleneQ-,—C₂₋₄alkenyleneQ-, —C₂₋₄alkynyleneQ- -QC₁₋₄alkyleneQ-, QC₂₋₄alkenyleneQ-or -QC₂₋₄alkynyleneQ-; and

Q is —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—, —N(R⁷)C(═O)— or—C(═O)N(R⁷)—;

wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroarylis optionally substituted;or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising the compounds of formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In a further aspect of the invention, there is provided a method oftreating or preventing neuropathic pain in a subject comprisingadministering a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In yet a further aspect of the invention there is provided a method oftreating or preventing a condition characterized by neuronalhypersensitivity in a subject comprising administering a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In yet another aspect of the invention, there is provided a method oftreating or preventing inflammatory pain in a subject comprisingadministering a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In a further aspect, the present invention provides a method of treatingor preventing impaired nerve conduction velocity in a subject comprisingadministering a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In yet a further aspect of the invention there is provided a method ofproducing analgesia in a subject comprising administering a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In still another aspect of the invention there is provided a method oftreating or preventing a cell proliferative disorder in a subjectcomprising administering a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

In a further aspect the present invention provides a method of treatingor preventing a disorder associated with an imbalance between boneresorption and bone formation in a subject comprising administering acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In yet another aspect the present invention provides a method oftreating a disorder associated with aberrant nerve regeneration in asubject comprising administering a compound of formula (I) or apharmaceutically acceptable salt thereof.

DESCRIPTION OF THE INVENTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by those of ordinary skillin the art to which the invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, preferred methods andmaterials are described. For the purposes of the present invention, thefollowing terms are defined below.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e. to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

As used herein, the term “about” refers to a quantity, level, value,dimension, size, or amount that varies by as much as 30%, 25%, 20%, 15%or 10% to a reference quantity, level, value, dimension, size, oramount.

As used herein, the term “AT₂ receptor” means an angiotensin H type 2(AT₂) receptor polypeptide that can bind angiotensin II and/or one ormore other ligands. The term “AT₂ receptor” encompasses vertebratehomologs of AT₂ receptor family members, including, but not limited to,mammalian, reptilian and avian homologs. Representative mammalianhomologs of AT₂ receptor family members include, but are not limited to,murine and human homologs.

The term “antagonist” as used herein refers to a compound that decreasesor inhibits the biological activity and/or function of an AT₂ receptor,including binding to the AT₂ receptor and blocking access to angiotensinII, inhibiting a gene that expresses AT₂ receptor, or inhibiting anexpression product of that gene. By the term “selective”, is meant thatthe compound binds to and/or inhibits AT₂ receptor activity to a greaterextent than binding and inhibition of the AT₁ receptor. In someinstances, selective refers to binding and/or inhibition of the AT₂receptor with little or no binding at the AT₁ receptor.

The term “allodynia” as used herein refers to the pain that results froma non-noxious stimulus i.e. pain due to a stimulus that does notnormally provoke pain. Examples of allodynia include, but are notlimited to, cold allodynia, tactile allodynia (pain due to lightpressure or touch), and the like.

The term “analgesia” is used herein to describe states of reduced painperception, including absence from pain sensations as well as states ofreduced or absent sensitivity to noxious stimuli. Such states of reducedor absent pain perception are induced by the administration of apain-controlling agent or agents and occur without loss ofconsciousness, as is commonly understood in the art. The term analgesiaencompasses the term “antinociception”, which is used in the art as aquantitative measure of analgesia or reduced pain sensitivity in animalmodels.

The term “anti-allodynia” is used herein to describe states of reducedpain perception, including absence from pain sensations as well asstates of reduced or absent sensitivity to non-noxious stimuli. Suchstates of reduced or absent pain perception are induced by theadministration of a pain-controlling agent or agents and occur withoutloss of consciousness, as is commonly understood in the art.

The term “causalgia” as used herein refers to the burning pain,allodynia, and hyperpathia after a traumatic nerve lesion, oftencombined with vasomotor and sudomotor dysfunction and later trophicchanges.

By “complex regional pain syndromes” is meant the pain that includes,but is not limited to, reflex sympathetic dystrophy, causalgia,sympathetically maintained pain, and the like.

By “condition characterized by neuronal hypersensitivity” is meantconditions that have symptoms of pain related to neuronalhypersensitivity and/or allodynia. Examples of this type of conditioninclude fibromyalgia and irritable bowel syndrome.

By “disorder associated with aberrant nerve regeneration” is meantdisorders in which there is abnormal axon outgrowth in neurons. Thisabnormal outgrowth may be associated with painful conditions includingbreast pain, interstitial cystitis, vulvodynia and cancerchemotherapy-induced neuropathies.

Throughout this specification, unless the context requires otherwise,the words “comprise”, “comprises” and “comprising” will be understood toimply the inclusion of a stated step or element or group of steps orelements but not the exclusion of any other step or element or group ofsteps or elements.

By “hyperalgesia” is meant an increased response to a stimulus that isnormally painful. A hyperalgesia condition is one that is associatedwith pain caused by a stimulus that is not normally painful.

By “neuropathic pain” is meant any pain syndrome initiated or caused bya primary lesion or dysfunction in the peripheral or central nervoussystem. Examples of neuropathic pain include, but are not limited to,thermal or mechanical hyperalgesia, thermal or mechanical allodynia,diabetic pain, entrapment pain, and the like.

The term “nociceptive pain” refers to the normal, acute pain sensationevoked by activation of nociceptors located in non-damaged skin, visceraand other organs in the absence of sensitization.

As used herein “inflammatory pain” refers to pain induced byinflammation. Such types of pain may be acute or chronic and can be dueto any number of conditions characterized by inflammation including,without limitation, burns including chemical, frictional or thermalburns, autoimmune diseases such as rheumatoid arthritis, osteoarthritisand inflammatory bowel disease including Crohn's disease and colitis, aswell as other inflammatory diseases including carditis, dermatitis,myositis, neuritis and collagen vascular diseases.

The term “pain” as used herein is given its broadest sense and includesan unpleasant sensory and emotional experience associated with actual orpotential tissue damage, or described in terms of such damage andincludes the more or less localized sensation of discomfort, distress,or agony, resulting from the stimulation of specialized nerve endings.There are many types of pain, including, but not limited to, lightningpains, phantom pains, shooting pains, acute pain, inflammatory pain,neuropathic pain, complex regional pain, neuralgia, neuropathy, and thelike (Dorland's Illustrated Medical Dictionary, 28^(th) Edition, W. B.Saunders Company, Philadelphia, Pa.). The goal of treatment of pain isto reduce the degree of severity of pain perceived by a treatmentsubject.

By the phrases “impaired NCV” or “impaired nerve conduction velocity”and the like is meant any nerve conduction demonstrably abnormal in anyone of the parameters assessed for normal nerve signal conduction.Whether the various parameters of NCV are normal is typically anassessment made by the relevant trained clinician. General background,terminology and procedures known to those in the art for evaluating NCVare described in “Proper performance and interpretation ofelectrodiagnostic studies’ Muscle Nerve. (2006) 33(3):436-439 and“Electrodiagnostic medicine listing of sensory, motor, and mixednerves.” Appendix J of Current Procedural Terminology (CPT) 2007,authored by The American Association of Neuromuscular &Electrodiagnostic Medicine and published by the American MedicalAssociation. Impaired or abnormal nerve conduction velocity is a symptomof nerve dysfunction or damage and may be causal to or a symptom of alarge number of diseases or disorders, particularly diseases ordisorders that exhibit diminished reflex responses and alteredperipheral sensation including paresthesia. As used herein,“paresthesia” refers to a sensation of tingling, prickling, weakness ornumbness in a subject's skin. It is also known as “pins and needles” ora limb “falling, asleep”. Paresthesia may be transient, acute or chronicand may occur alone or be accompanied by other symptoms such as pain.

As used herein, the term “cell proliferative disorder” refers todiseases or conditions where unwanted or damaged cells are not removedby normal cellular process, or diseases or conditions in which cellsundergo aberrant, unwanted or inappropriate proliferation.

Disorders characterized by inappropriate cell proliferation include, forexample, inflammatory conditions such as inflammation arising from acutetissue injury including, for example, acute lung injury, cancerincluding cancers characterized by tumors, autoimmune disorders, tissuehypertrophy and the like.

The term “disorder associated with an imbalance between bone resorptionand bone formation” includes disorders where there is insufficientdevelopment of bone mass, excessive bone resorption and insufficientbone formation during remodelling. An exemplary disorder associated withan imbalance between bone resorption and bone formation is osteoporosis.

As used herein, the term “alkyl” refers to a straight chain or branchedsaturated hydrocarbon group having 1 to 10 carbon atoms. Whereappropriate, the alkyl group may have a specified number of carbonatoms, for example, C₁₋₆alkyl which includes alkyl groups having 1, 2,3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examplesof suitable alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl,3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl,octyl, nonyl and decyl.

As used herein, the term “alkenyl” refers to a straight-chain orbranched hydrocarbon group having one or more double bonds betweencarbon atoms and having 2 to 10 carbon atoms. Where appropriate, thealkenyl group may have a specified number of carbon atoms. For example,C₂-C₆ as in “C₂-C₆alkenyl” includes groups having 2, 3, 4, 5 or 6 carbonatoms in a linear or branched arrangement. Examples of suitable alkenylgroups include, but are not limited to, ethenyl, propenyl, isopropenyl,butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl,heptenyl, octenyl, nonenyl and decenyl.

As used herein, the term “alkynyl” refers to a straight-chain orbranched hydrocarbon group having one or more triple bonds and having 2to 10 carbon atoms. Where appropriate, the alkynyl group may have aspecified number of carbon atoms. For example, C₂-C₆ as in“C₂-C₆alkynyl” includes groups having 2, 3, 4, 5 or 6 carbon atoms in alinear or branched arrangement. Examples of suitable alkynyl groupsinclude, but are not limited to ethynyl, propynyl, butynyl, pentynyl andhexynyl.

As used herein, the term “cycloalkyl” refers to a saturated cyclichydrocarbon. The cycloalkyl ring may include a specified number ofcarbon atoms. For example, a 3 to 8 membered cycloalkyl group includes3, 4, 5, 6, 7 or 8 carbon atoms. Examples of suitable cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, the term “cycloalkenyl” refers to an unsaturated cyclichydrocarbon. The cycloalkenyl ring may include a specified number ofcarbon atoms. For example, a 5 to 8 membered cycloalkenyl group includes5, 6, 7 or 8 carbon atoms. The cycloalkenyl group has one or more doublebonds and when more than one double bond is present, the double bondsmay be unconjugated or conjugated, however the cycloalkenyl group is notaromatic. Examples of suitable cycloalkenyl groups include, but are notlimited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl andcyclooctatrienyl rings.

As used herein, the term “aryl” is intended to mean any stable,monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms ineach ring, wherein at least one ring is aromatic. Examples of such arylgroups include, but are not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, fluorenyl, phenanthrenyl, biphenyl andbinaphthyl.

As used herein, the term “alkylene” refers to a divalent saturatedhydrocarbon chain having 1 to 6 carbon atoms. Where appropriate, thealkylene group may have a specified number of carbon atoms, for example,C₁ alkylene includes alkylene groups having 1, 2, 3, 4, 5 or 6 carbonatoms in a linear arrangement. Examples of suitable alkylene groupsinclude, but are not limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH₂CH₂—.

As used herein, the term “alkenylene” refers to a divalent unsaturatedhydrocarbon chain having 2 to 6 carbon atoms and at least one doublebond. Where appropriate, the alkenylene group may have a specifiednumber of carbon atoms, for example, C₂₋₆alkenylene includes alkenylenegroups having 2, 3, 4, 5 or 6 carbon atoms in a linear arrangement. Thedouble bonds may be in either E or Z configuration. Examples of suitablealkenylene groups include, but are not limited to, —CH═CH—, —CH═CHCH₂—,—CH₂CH═CH—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—,—CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—, —CH₂CH₂CH₂CH═CH—,—CH═CHCH₂CH₂CH₂CH₂— —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,—CH₂CH₂CH₂CH═CHCH₂— and —CH₂CH₂CH₂CH₂CH═CH—.

As used herein, the term “alkynylene” refers to a divalent unsaturatedhydrocarbon chain having 2 to 6 carbon atoms and at least one triplebond. Where appropriate, the alkynylene group may have a specifiednumber of carbon atoms, for example, C₂₋₆alkynylene includes alkynylenegroups having 2, 3, 4, 5 or 6 carbon atoms in a linear arrangement.Examples of suitable alkynylene groups include, but are not limited to,—C≡C—, —C≡CCH₂—, —CH₂C≡C—, —C≡CCH₂CH₂—, —CH₂C≡CCH₂—, —CH₂CH₂C≡C—,—C≡CCH₂CH₂CH₂—, —CH₂C≡CCH₂CH₂—, —CH₂CH₂C≡CCH₂—, —CH₂CH₂CH₂C≡C—,—C≡CCH₂CH₂CH₂CH₂— —CH₂C≡CCH₂CH₂CH₂—, —CH₂CH₂C≡CCH₂CH₂—,—CH₂CH₂CH₂C≡CCH₂— and —CH₂CH₂CH₂CH₂C≡C—.

In some embodiments, one or more “—CH₂—” groups in an alkylene,alkenylene or alkynylene group may be replaced by a heteroatom or agroup containing a heteroatom including —O—, —S—, —NH—, —NR—, —S(O)—,—S(O)₂—, —C(═O)—, —C(═O)NH— and —NHC(═O)—.

The term “benzyl” where used herein refers to a phenylmethylene group,C₆H₅CH₂—.

As used herein, the term “halogen” or “halo” refers to fluorine(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo).

The term “heterocyclic” or “heterocyclyl” as used herein, refers to acyclic hydrocarbon in which one to four carbon atoms have been replacedby heteroatoms independently selected from the group consisting of N,N(R), S, S(O), S(O)₂ and O. A heterocyclic ring may be saturated orunsaturated but not aromatic. A heterocyclic group may also be part of aspirocyclic group containing 1, 2 or 3 rings, two of which are in a“spiro” arrangement. Examples of suitable heterocyclyl groups includeazetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl,2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolyl,oxathiolyl, dioxanyl, dioxinyl, dioxazolyl, oxathiozolyl, oxazolonyl,piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, dithianyl,trithianyl and oxazinyl.

The term “heteroaryl” as used herein, represents a stable monocyclic,bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein atleast one ring is aromatic and at least one ring contains from 1 to 4heteroatoms selected from the group consisting of O, N and S. Heteroarylgroups within the scope of this definition include, but are not limitedto, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl,pyrazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl, benzotriazolyl,furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane,benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl,imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl,1,2,4-triazinyl, 1,2,4,5-tetrazinyl and tetrazolyl. Particularheteroaryl groups have 5- or 6-membered rings, such as pyrazolyl,furanyl, thienyl, oxazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl,isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and1,2,4-oxadiazolyl and 1,2,4-thiadiazolyl.

Each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl and heteroaryl whether an individual entity or as part of alarger entity may be optionally substituted with one or more optionalsubstituents selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, C₃₋₆cycloalkyl, oxo (═O), —OH, —SH, C₁₋₆alkylO—,C₂₋₆alkenylO—, C₃₋₆cycloalkylO—, C₁₋₆alkylS—, C₂₋₆alkenylS—,C₃₋₆cycloalkylS—, —CO₂H, —CO₂C₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —NH(phenyl), —N(phenyl)₂, oxo, —CN, —NO₂, -halogen,—CF₃, —OCF₃, —SCF₃, —CHF₂, —OCHF₂, —SCHF₂phenyl heterocyclyl,-heteroaryl Oheteroaryl Oheterocyclyl Ophenyl, —C(═O)phenyl,—C(═O)C₁₋₆alkyl. Examples of suitable substituents include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, vinyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy,hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fluoro,chloro, bromo, iodo, cyano, nitro, —CO₂H, —CO₂CH₃, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy,difluoromethylthio, morpholino, amino, methylamino, dimethylamino,phenyl, phenoxy, phenylcarbonyl, benzyl and acetyl.

The term “carboxylic acid bioisotere” refers to a group which isphysiochemically or topologically similar to carboxylic acid orcarboxylate group. Examples of suitable carboxylic acid or carboxylateisosteres include, but are not limited to, tetrazole, tetrazolate,—CONH-tetrazole, oxadiazole, phosphate (—PO₃H₂), —C(OH)(CF₃)₂, N-(arylor heteroaryl)-sulfonamides, acylsulfonamides and sulfonic acid (—SO₃H)[See Patani and LaVoie, 1996]. Examples of sulfonamide isostericequivalents of carboxy groups include C(═O)NHSO₂R^(a),—C(═O)NHSO₂N(R^(a))₂, —C(═O)NHSO₂NH(R^(a)), —SO₂NHC(═O)R^(a),—SO₂NHC(═O)NHR^(a), —SO₂NHR^(a) and —NHSO₂R^(a), where R^(a) is selectedfrom the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl,aryl, heterocyclyl, heteroaryl and —CF₃.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. It will be appreciated however thatnon-pharmaceutically acceptable salts also fall within the scope of theinvention since these may be useful as intermediates in the preparationof pharmaceutically acceptable salts or may be useful during storage ortransport. Suitable pharmaceutically acceptable salts include, but arenot limited to, salts of pharmaceutically acceptable inorganic acidssuch as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric,sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptableorganic acids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic,succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic,benezenesulphonic, salicylic sulphanilic, aspartic, glutamic, edetic,stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic andvaleric acids.

Base salts include, but are not limited to, those formed withpharmaceutically acceptable cations, such as sodium, potassium, lithium,calcium, magnesium, ammonium and alkyl ammonium.

Basic nitrogen-containing groups may be quaternized with such agents aslower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl and diethylsulfate; and others.

It will also be recognised that compounds of the invention may possessasymmetric centres and are therefore capable of existing in more thanone stereoisomeric form. The invention thus also relates to compounds insubstantially pure isomeric form at one or more asymmetric centres eg.,greater than about 90% ee, such as about 95% or 97% ee or greater than99% ee, as well as mixtures, including racemic mixtures, thereof. Suchisomers may be prepared by asymmetric synthesis, for example usingchiral intermediates, or by chiral resolution. The compounds of theinvention may exist as geometric isomers. The invention also relates tocompounds in substantially pure cis (Z) or trans (E) or mixturesthereof.

COMPOUNDS OF THE INVENTION

In a first aspect of the present invention there is provided a compoundof formula (I):

wherein

X is —CHR⁴—, —CH₂CHR⁴— or —C(═O)—;

R¹ is —C(═O)CHR⁵R⁶, —C(═O)NR⁵R⁶, —C(═O)CH₂CHR⁵R⁶, —C(═O)CH═CR⁵R⁶,—C(═S)CHR⁵R⁶, —C(═S)NR⁵R⁶, —C(═S)CH₂CHR⁵R⁶, —C(═S)CH═CR⁵R⁶,—C(═NR⁷)CHR⁵R⁶, —C(═NR⁷)NR⁵R⁶, —C(═NR⁷)CH₂CHR⁵R⁶ or —C(═NR⁷)CH═CR⁵R⁶;R² is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)R⁸, —C(═O)NHR⁷,—SO₂N(R⁷)₂, —W-cycloalkyl, —W-cycloalkenyl, —W-aryl, —W-heterocyclyl,—W-heteroaryl, —W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl,—W—Z—Y-heterocyclyl or —W—Z—Y-heteroaryl;R³ is a carboxylic acid, —CH₂CO₂H, —C(═O)C(═O)OH, —CH₂OH, —C(═O)NH₂,—CH₂C(═O)NH₂, —CN, —CH₂CN, a carboxylic acid biostere or a—CH₂-carboxylic acid bioisotere;R⁴ is hydrogen or together with R² forms a fused cycloalkyl,cycloalkenyl, aryl, heterocyclyl or heteroaryl ring optionallysubstituted with, one or two substituents selected from —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —C₁₋₆alkyleneR⁹, —C₂₋₆alkenyleneR⁹,—C₂₋₆alkynyleneR⁹, —OC₀₋₆alkyleneR⁹, —OC₂₋₆alkenyleneR⁹,—OC₂₋₆alkynyleneR⁹, —C(═O)C₀₋₆alkyleneR⁹, —C(═O)C₂₋₆alkenyleneR⁹,—C(═O)C₂₋₆alkynyleneR⁹, —C(═O)OC₀₋₆alkyleneR⁹, —C(═O)OC₂₋₆alkenyleneR⁹,—C(═O)OC₂₋₆alkynyleneR⁹, —SO₂NHC₀₋₆alkyleneR⁹, —SO₂NHC₂₋₆alkenyleneR⁹,—SO₂NHC₂₋₆alkynyleneR⁹, —NHSO₂C₀₋₆alkyleneR⁹, —NHSO₂C₂₋₆alkenyleneR⁹,—NHSO₂C₂₋₆alkynyleneR⁹, —NH(═O)NHR¹⁰, —NHC(═O)OR¹⁰ or —CH(OH)CH(OH)R¹⁰;R⁵ and R⁶ are independently selected from hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —CH₂cycloalkyl, —CH₂cycloalkenyl, —CH₂aryl,—CH₂heterocyclyl and —CH₂heteroaryl; provided that both R⁵ and R⁶ arenot hydrogen;R⁷ is hydrogen, —C₁₋₆alkyl, aryl or —C₁₋₆alkylenearyl;R⁸ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl or —C₁₋₆alkylenearyl;R⁹ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl;R¹⁰ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl,aryl, heterocyclyl or heteroaryl;W is a covalent bond, —SO—, —SO₂— —C(═O)—, —C(═O)N(R⁷)—, —C₁₋₄alkylene-,—C₂₋₄alkenylene-, —C₂₋₄alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-,—C₁₋₄alkyleneQ-, —C₂₋₄-alkenyleneQ- or —C₂₋₄alkynyleneQ-;Z is -cycloalkyl-, -cycloalkenyl-, -aryl-, -heterocyclyl- or-heteroaryl-;Y is a covalent bond, —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—,—N(R⁷)C(═O)—, —C(═O)N(R⁷)—, —C₁₋₃alkylene-, —C₂₋₃alkenylene-,—C₂₋₃alkynylene-; —C₁₋₃alkyl ene QC₁₋₃alkylene-, -QC₁₋₄alkylene-,-QC₂₋₄alkenylene-, -QC₂₋₄alkynylene-, —C₁₋₄alkyleneQ-,—C₂₋₄alkenyleneQ-, —C₂₋₄alkynyleneQ- -QC₁₋₄alkyleneQ-, QC₂₋₄alkenyleneQ-or -QC₂₋₄alkynyleneQ-; and

Q is —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—, —N(R⁷)C(═O)— or—C(═O)N(R⁷)—;

wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroarylis optionally substituted;or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention, the compound of formula(I) is a compound of formula (IA):

wherein

X is —CHR⁴—, —CH₂CHR⁴— or —C(═O)—;

R¹ is —C(═O)CHR⁵R⁶, —C(═O)NR⁵R⁶, —C(═O)CH₂CHR⁵R⁶, —C(═O)CH═CR⁵R⁶,—C(═S)CHR⁵R⁶, —C(═S)NR⁵R⁶, —C(═S)CH₂CHR⁵R⁶, —C(═S)CH═CR⁵R⁶,—C(═NR⁷)CHR⁵R⁶, —C(═NR⁷)NR⁵R⁶, —C(═NR⁷)CH₂CHR⁵R⁶ or —C(═NR⁷)CH═CR⁵R⁶;R² is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)R⁸, —C(═O)NHR⁷,—SO₂N(R⁷)₂, —W-cycloalkyl, —W-cycloalkenyl, —W-aryl, —W-heterocyclyl,—W-heteroaryl, —W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl,—W—Z—Y-heterocyclyl or —W—Z—Y-heteroaryl;R³ is a carboxylic acid, —CH₂CO₂H, —C(═O)C(═O)OH or a carboxylic acidbioisotere;R⁴ is hydrogen or together with R² forms a fused cycloalkyl,cycloalkenyl, aryl, heterocyclyl or heteroaryl ring optionallysubstituted with one or two substituents selected from —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —C₁₋₆alkyleneR⁹, —C₂₋₆alkenyleneR⁹,—C₂₋₆alkynyleneR⁹, —OC₀₋₆alkyleneR⁹, —OC₂₋₆alkenyleneR⁹,—OC₂₋₆alkynyleneR⁹, —C(═O)C₀₋₆alkyleneR⁹, —C(═O)C₂₋₆alkenyleneR⁹,—C(═O)C₂₋₆alkynyleneR⁹, —C(═O)OC₀₋₆alkyleneR⁹, —C(═O)OC₂₋₆alkenyleneR⁹,—C(═O)OC₂₋₆alkynyleneR⁹, —SO₂NHC₀₋₆alkyleneR⁹, —SO₂NHC₂₋₆alkenyleneR⁹,—SO₂NHC₂₋₆alkynyleneR⁹, —NHSO₂C₀₋₆alkyleneR⁹, NHSO₂C₂₋₆alkenyleneR⁹,—NHSO₂C₂₋₆alkynyleneR⁹, —NH(═O)NHR¹⁰, —NHC(═O)OR¹⁰ or —CH(OH)CH(OH)R¹⁰;R⁵ and R⁶ are independently selected from, hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —CH₂cycloalkyl, —CH₂cycloalkenyl, —CH₂aryl,—CH₂heterocyclyl and —CH₂heteroaryl; provided that both R⁵ and R⁶ arenot hydrogen;R⁷ is hydrogen, —C₁₋₆alkyl, aryl or —C₁₋₆alkylenearyl;R⁸ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl or —C₁₋₆alkylenearyl;R⁹ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl;R¹⁰ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl,aryl, heterocyclyl or heteroaryl;W is a covalent bond, —SO—, —SO₂—, —C(═O)—, —C(═O)N(R⁷)—,—C₁₋₄alkylene-, —C₂₋₄alkenylene-, —C₂₋₄alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-, —C₁₋₄alkyleneQ-, —C₂₋₄alkenyleneQ- or —C₂₋₄alkynyleneQ-;Z is -cycloalkyl-, -cycloalkenyl-, -aryl-, -heterocyclyl- or-heteroaryl-;Y is a covalent bond, —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—,—N(R⁷)C(═O)—, —C(═O)N(R⁷)—, —C₁₋₃alkylene-, —C₂₋₃alkenylene-,—C₂₋₃alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-, -QC₁₋₄alkylene-,-QC₂₋₄alkenylene-, -QC₂₋₄alkynylene-, —C₁₋₄alkyleneQ-,—C₂₋₄alkenyleneQ-, —C₂₋₄alkynyleneQ- -QC₁₋₄alkyleneQ-, QC₂₋₄alkenyleneQ-or -QC₂₋₄alkynyleneQ-; and

Q is —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—, —N(R⁷)C(═O)— or—C(═O)N(R⁷)—;

wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroarylis optionally substituted;or a pharmaceutically acceptable salt thereof.

In particular embodiments of formula (I), one or more of the followingapplies:

X is —CHR⁴—, especially —CH₂—;R¹ is —C(═O)CHR⁵R⁶, —C(═O)NR⁵R⁶, especially —C(═O)CH(aryl)(aryl),—C(═O)CH(aryl)(cycloalkyl), —C(═O)CH(cycloalkyl)(cycloalkyl),—C(═O)N(aryl)(aryl), —C(═O)N(aryl)(cycloalkyl) or—C(═O)N(cycloalkyl)(cycloalkyl), more especially—C(═O)CH(phenyl)(phenyl), —C(═O)CH(phenyl)(cyclohexyl),—C(═O)CH(cyclohexyl)(cyclohexyl), —C(═O)N(phenyl)(phenyl),—C(═O)N(phenyl)(cyclohexyl) or —C(═O)N(cyclohexyl)(cyclohexyl), evenmore especially —C(═O)CH(phenyl)(phenyl) or —C(═O)N(phenyl)(phenyl),most especially —C(═O)CH(phenyl)(phenyl);R² is —C₁₋₆alkyl, —C₂₋₆alkenyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, heterocyclylaryl, —C₁₋₄alkylenecycloalkyl,—C₁₋₄alkylenecycloalkenyl, —C₁₋₄alkylenearyl, —C₁₋₄alkyleneheterocyclyl,—C₁₋₄alkyleneheteroaryl, —C₂₋₄alkenylenecycloalkyl,—C₂₋₄alkenylenecycloalkenyl, —C₂₋₄alkenylenearyl,—C₂₋₄alkenyleneheterocyclyl, —C₂₋₄alkenyleneheteroaryl,—C₂₋₄alkynylenecycloalkyl, —C₂₋₄alkynylenecycloalkenyl,—C₂₋₄alkynylenearyl, —C₂₋₄alkynyleneheterocyclyl,—C₂₋₄alkynyleneheteroaryl, -heterocyclylaryl heteroarylarylheterocyclylC₁₋₃alkylenearyl, —C₁₋₃alkyleneheterocyclylaryl,—C₁₋₃alkyleneheteroarylaryl —CH₂C(═O)NHCH₂cycloalkyl,—CH₂C(═O)NHCH₂cycloalkenyl, —CH₂C(═O)NHCH₂aryl,—CH₂C(═O)NHCH₂heterocyclyl, —CH₂C(═O)NHCH₂heteroaryl,—C(═O)NHC₁₋₃alkylenecycloalkyl, —C(═O)NHC₁₋₃alkylenecycloalkenyl,—C(═O)NHC₁₋₃alkylenearyl, —C(═O)NHC₁₋₃alkyleneheterocyclyl,—C(═O)NHC₁₋₃alkyleneheteroaryl, —CH₂SO₂C₁₋₃alkylenecycloalkyl,—CH₂SO₂C₁₋₃alkylenecycloalkenyl, —CH₂SO₂C₁₋₃alkylenearyl,—CH₂SO₂C₁₋₃alkyleneheterocyclyl, —CH₂SO₂C₁₋₃alkylenehetero aryl,—CH₂OC₁₋₃alkylenecycloalkyl, —CH₂OC₁₋₃alkylenecycloalkenyl,—CH₂OC₁₋₃alkylenearyl, —CH₂OC₁₋₃alkyleneheterocyclyl or—CH₂OC₁₋₃alkyleneheteroaryl; especially —C₁₋₆alkyl, —C₂₋₆alkenylcycloalkyl, -cycloalkenyl aryl heterocyclyl heteroaryl,—C₁₋₄alkylenecycloalkyl, —C₁₋₄alkylenecycloalkenyl, —C₁₋₄alkylenearyl,—C₄alkyleneheterocyclyl, —C₁₋₄alkyleneheteroaryl,—C₂₋₄alkenylenecycloalkyl, —C₂₋₄alkenylenecycloalkenyl,—C₂₋₄alkenylenearyl, —C₂₋₄alkenyleneheterocyclyl,—C₂₋₄alkenyleneheteroaryl, -heterocyclylaryl heteroarylarylheterocyclylC₁₋₃alkylenearyl hetero arylC₁₋₃alkylenearyl,—C₁₋₃alkyleneheterocyclylaryl, or —C₁₋₃alkyleneheteroarylaryl, whereineach cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl isoptionally substituted with one or two substituents selected from—C₁₋₆alkyl, —OC₁₋₆alkyl or -halo; especially where R² is phenyl, benzyl,—CH₂CH₂-phenyl, —CH₂CH═CH-phenyl, —CH₂C≡C-phenyl,—CH₂C≡C-4-fluoro-phenyl, —CH₂CH₂C≡Cphenyl, —CH₂CH₂C≡C-4-fluorophenyl,—CH₂CH₂CH₂phenyl, -2-methylbutyl 5-(3-methyl-1-phenylpyrazole)3-(1,5-diphenylpyrazole) 3-(5-phenylpyrazole)3-(5-methyl-1-phenylpyrazole), 3-(5-(1-methylethyl)-1-phenylpyrazole,-2-(5-phenyloxazole) 5-(5-benzyloxazole) 5-(1-benzyl-3-methylpyrazole)3-(1-benzyl-5-methylpyrazole, —CH₂-4-(2-phenyloxazole),-5-(1-benzyl)-3-trifluoromethylpyrazole and-5-(1-benzyl-3-methylpyrazole);R³ is —CO₂H, —CH₂CO₂H, —C(═O)C(═O)OH, —C(═O)NH₂, —CN,—C(═O)NHSO₂C₁₋₆allyl, —C(═O)NHSO₂phenyl, —C(═O)NHSO₂N(C₁₋₆alkyl)₂ or—C(═O)NHSO₂CF₃, especially —CO₂H, —CH₂CO₂H, —C(═O)NHSO₂C₁₋₄alkyl,—C(═O)NHSO₂N(C₁₋₃alkyl)₂, —C(═O)NHSO₂phenyl or —C(═O)NHSO₂CF₃, moreespecially —CO₂H;R⁴ is hydrogen or R⁴ and R² together form a fused aryl, heterocyclyl orheteroaryl ring optionally substituted with one or two substituentsselected from -aryl, —C₁₋₃alkylenearyl, -Oaryl, —OC₁₋₃alkylenearyl and—C(═O)OC₁₋₃alkylenearyl; especially a fused heterocyclyl or heteroarylring optionally substituted with phenyl, benzyl, -Obenzyl, or—CO₂benzyl;R⁵ and R⁶ are independently selected from phenyl and cyclohexyl,especially where both R⁵ and R⁶ are phenyl;R⁷ is hydrogen, methyl, ethyl or phenyl.

In some embodiments, R³ has an S stereochemistry.

In one embodiment, the compound of formulae (I) or (IA) is a compound offormula (II):

whereinR¹ is —C(═O)CHR⁵R⁶, —C(═O)NR⁵R⁶, —C(═O)CH₂CHR⁵R⁶, —C(═O)CH═CR⁵R⁶,—C(═S)CHR⁵R⁶, —C(═S)NR⁵R⁶, —C(═S)CH₂CHR⁵R⁶, —C(═S)CH═CR⁵R⁶,—C(═NR⁷)CHR⁵R⁶, —C(═NR⁷)NR⁵R⁶, —C(═NR⁷)CH₂CHR⁵R⁶ or —C(═NR⁷)CH═CR⁵R⁶;R² is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)R⁸, —C(═O)NHR⁷,—SO₂N(R⁷)₂, —W-cycloalkyl, —W-cycloalkenyl, —W-aryl, —W-heterocyclyl,—W-heteroaryl, —W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl,—W—Z—Y-heterocyclyl or —W—Z—Y-heteroaryl;R³ is a carboxylic acid, —CH₂CO₂H, —C(═O)C(═O)OH, —C(═O)NH₂, —CN or acarboxylic acid bioisotere;R⁴ is hydrogen or together with R² forms a fused cycloalkyl,cycloalkenyl, aryl, heterocyclyl or heteroaryl ring optionallysubstituted with one or two substituents selected from —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —C₁₋₆alkyleneR⁹, —C₂₋₆alkenyleneR⁹,—C₂₋₆alkynyleneR⁹, —OC₀₋₆alkyleneR⁹, —OC₂₋₆alkenyleneR⁹,—OC₂₋₆alkynyleneR⁹, —C(═O)C₀₋₆alkyleneR⁹, —C(═O)C₂₋₆alkenyleneR⁹,—C(═O)C₂₋₆alkynyleneR⁹, —C(═O)OC₀₋₆alkyleneR⁹, —C(═O)OC₂₋₆alkenyleneR⁹,—C(═O)OC₂₋₆alkynyleneR⁹, —SO₂NHC₀₋₆alkyleneR⁹, —SO₂NHC₂₋₆alkenyleneR⁹,—SO₂NHC₂₋₆alkynyleneR⁹, —NHSO₂C₀₋₆alkyleneR⁹, —NHSO₂C₂₋₆alkenyleneR⁹,—NHSO₂C₂₋₆alkynyleneR⁹, —NH(═O)NHR¹⁰, —NHC(═O)OR¹⁰ or —CH(OH)CH(OH)R¹⁰;R⁵ and R⁶ are independently selected from hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —CH₂cycloalkyl, —CH₂cycloalkenyl, —CH₂aryl,—CH₂heterocyclyl and —CH₂heteroaryl; provided that both R⁵ and R⁶ arenot hydrogen;R⁷ is hydrogen, —C₁₋₆alkyl, aryl or —C₁₋₆alkylenearyl;R⁸ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl or —C₁₋₆alkylenearyl;R⁹ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl;R¹⁰ is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl,aryl, heterocyclyl or heteroaryl;W is a covalent bond, —SO—, —SO₂— —C(═O)N(R⁷)—, C₁₋₄alkylene-,—C₂₋₄alkenylene-, —C₂₋₄alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-,—C₁₋₄alkyleneQ-, —C₂₋₄alkenyleneQ- or —C₂₋₄alkynyleneQ-;Z is -cycloalkyl-, -cycloalkenyl-, -aryl-, -heterocyclyl- or-heteroaryl-;Y is a covalent bond, —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—,—N(R⁷)C(═O)—, —C(═O)N(R⁷)—, —C₁₋₃alkylene-, —C₂₋₃alkenylene-,—C₂₋₃alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-, -QC₁₋₄alkylene-,-QC₂₋₄alkenylene-, -QC₂₋₄alkynylene-, —C₁₋₄alkyleneQ-,—C₂₋₄alkenyleneQ-, —C₂₋₄alkynyleneQ- -QC₁₋₄alkyleneQ-,-QC₂₋₄alkenyleneQ- or -QC₂₋₄alkynyleneQ-; and

Q is —O—, —S—, —SO—, —SO₂— —N(R⁷)—, —C(═O)—, —N(R⁷)C(═O)— or—C(═O)N(R⁷)—;

wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroarylis optionally substituted;or a pharmaceutically acceptable salt thereof.

Particular compounds of formula (I) are:

Compound X R¹ R² R³ R⁴ R²/R⁴ 1 —CHR⁴— —C(O)CH(phenyl)₂ — —CO₂H (S) —

2 —CHR⁴— —C(O)CH(phenyl)₂ — —CO₂H (S) —

3 —CHR⁴— —C(O)CH(phenyl)₂ — —CO₂H (S) —

4 —CHR⁴— —C(O)CH(phenyl)₂ -phenyl —CO₂H (S) H — 5 —CHR⁴——C(O)CH(phenyl)₂ —CH₂phenyl —CO₂H (S) H — 6 —CHR⁴— —C(O)CH(phenyl)₂-3-(1,5-diphenyl-pyrazole) —CO₂H (S) H — 7 —CHR⁴— —C(O)CH(phenyl)₂-5-(3-methyl-1-phenyl- —CO₂H (S) H — pyrazole) 8 —CHR⁴— —C(O)CH(phenyl)₂—CH₂CH₂phenyl —CO₂H (S) H — 9 —CHR⁴— —C(O)CH(phenyl)₂ —CH₂CH═CHphenyl—CO₂H (S) H — 10 —CHR⁴— —C(O)CH(phenyl)₂ —CH₂CH₂CH₂phenyl —CO₂H (S) H —11 —CHR⁴— —C(O)CH(phenyl)₂ -3-(1-phenylpyrazole) —CO₂H (S) H — 12 —CHR⁴——C(O)CH(phenyl)₂ -3-(5-methyl-1-phenyl- —CO₂H (S) H — pyrazole) 13—CHR⁴— —C(O)CH(phenyl)₂ -3-(5-(1-methylethyl)-1- —CO₂H (S) H —phenylpyrazole) 14 —CHR⁴— —C(O)CH(phenyl)₂ -2-(5-phenyl-1,3-oxazole)—CO₂H (S) H — 15 —CHR⁴— —C(O)CH(phenyl)₂ -2-(5-benzyl-1,3-oxazole) —CO₂H(S) H — 16 —CHR⁴— —C(O)CH(phenyl)₂ -5-(1-benzyl-3-methyl- —CO₂H (S) H —pyrazole) 17 —CHR⁴— —C(O)CH(phenyl)₂ -3-(1-benzyl-5-methyl- —CO₂H (S) H— pyrazole) 18 —CHR⁴— —C(O)CH(phenyl)₂ -2-methylbutyl —CO₂H (S) H — 19—CHR⁴— —C(O)CH(phenyl)₂ —CH₂-4-(2-phenyl-1,3- —CO₂H (S) H — oxazole) 20—CH₂CHR⁴— —C(O)CH(phenyl)₂ —CH₂CH₂phenyl —CO₂H (S) H — 21 —CH₂CHR⁴——C(O)CH(phenyl)₂ — —CO₂H (S) —

22 —CHR⁴— —C(O)CH(phenyl)₂ — —CO₂H (S) —

23 —CHR⁴— —C(O)CH(phenyl)₂ -5-(1-benzyl)-3- —CO₂H (S) H —trifluoromethylpyrazolyl 24 —CHR⁴— —C(O)CH(phenyl)₂ —CH₂C≡C-phenyl —CO₂H(S) H — 25 —CHR⁴— —C(O)CH(phenyl)₂ —CH₂C≡C-4-fluorophenyl —CO₂H (S) H —26 —CHR⁴— —C(O)CH(phenyl)₂ —CH₂CH₂C≡C-phenyl —CO₂H (S) H — 27 —CHR⁴——C(O)CH(phenyl)₂ —CH₂CH₂C≡C-4- —CO₂H (S) H — fluorophenyl 28 —CHR⁴——C(O)CH(phenyl)₂ -5-(1-benzyl)-3-methyl- —CONHSO₂N(CH₃)₂ H — pyrazolyl *indicates the shared bond between the fused ring and the piperazinering.

Particular compounds of the formula (I) include compounds 4, 5, 6, 7, 8,9, 10, 16, 23, 24, and 26, especially compounds 4, 5, 7, 10, 16 and 23.

In some embodiments, the compounds of formula (I) are selective AT₂receptor antagonists. In particular embodiments, the selective AT₂receptor antagonists have an IC₅₀ at the AT₂ receptor of ≦100 nM and anIC₅₀ at the AT₁ receptor of >100,000 nM (10 μM) using the assaymethodologies described in Biological Examples 1 and 2.

The compounds of the invention are made by methods known in the art fromcommercially available starting materials.

For preparation of the piperazine compounds, a suitable startingmaterial is 1N-protected-piperazine-2-carboxylic acid or its methylester, the enantiomers of which are commercially available.

R¹ may be introduced either before the introduction of R² or after theintroduction of R², or after formation of the fused heterocyclyl orheteroaryl ring. If R² is introduced prior to the introduction of R¹, itmay be necessary to protect the ring nitrogen during the alkylationreaction. Suitable nitrogen protecting groups are known in the art, forexample, in Greene & Wutz, Protective Groups in Organic Synthesis, ThirdEdition, John Wiley & Sons, 1999. A suitable nitrogen protecting groupis t-butoxycarbonyl (Boc).

R¹ may be introduced by amide formation with a suitable carboxylic acidand the ring nitrogen. Amide formation is well known in the art and mayinvolve the activation of the carboxylic acid, for example, the carboxygroup is activated by formation of an acid chloride, carbodiimide,triazole or a uronium or phosphonium salt of a non-nucleophilic anion.Suitable activating groups are well known in the art includingdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDCI),1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt),ethyl-2-cyano-2-cyano-2-(hydroxyimino)acetate (Oxyma Pure),O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluorophosphate (HCTU),O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate(TBTU), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP);(benzotriazol-1-yloxy)-tris-(dimethylamino)phosphoniumhexafluorophosphate (BOP),(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)-dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU) andO-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU).

R² may be introduced by alkylation or arylation reactions as known inthe art. For example, an alkylhalide or arylalkylhalide may be used toalkylate the unprotected piperazine nitrogen atom. An aryl group may bedirectly bonded to the unprotected piperazine nitrogen, for example, bycopper catalysed arylation using an arylboronic acid in the presence ofa copper catalyst such as copper diacetate (Cu(OAc)₂).

When R² is a heteroaryl or heterocyclyl group it may be introduceddirectly by means of an appropriate halide or heteroaryl boronic acid ormay be prepared in situ. For example, the unprotected piperazinenitrogen may be alkylated with a suitably functionalized alkyl oralkylaryl group, for example, to provide a 1,3-diketobutyl substituentor a 3-phenyl-3-keto-1-thiomethyl-1-propenyl substituent. Addition of ahydrazine or a substituted hydrazine gives a pyrazole substituent as R².

Where R² forms an amide with the piperazine ring nitrogen atom, R² maybe introduced by methods known for amide formation, such as thosedescribed for introduction of R¹.

Fused ring systems may also be readily prepared by literatureprocedures. For example, imidazo[1,2-a]piperazine carboxylic acids andtriazolo[4,3-a]piperazine carboxylic acids may be prepared from suitableN-protected piperazine carboxylic acid imino ethers by reaction withsubstituted or unsubstituted propargylamine or ethynylamine or acetichydrazide or aroylhydrazide respectively [McCort & Pascal, Tet. Lett.,1992, 33(31):4443-4446 and WO 2009158394].

Alternatively, a 2-(aminomethyl)pyrazine can be reacted with anaroylchloride such as PhCOCl to provide an aryl amide that issubsequently cyclised with POCl₃ to give an aryl substitutedimidazo[1,2-a]pyrazine ring system, which may be subsequently reducedwith H₂ to give an imidazo[1,2-a]piperazine ring system [WO 2009158394].

Another approach includes alkylation of an imidazole-2-aldehyde with asuitable N-protected 2-hydroxyethylamine. The resulting5-(2-hydroxyethyl-aminomethyl)imidazole hydroxy group is displaced bychloride using thionyl chloride and ring cyclization occurs to producean imidazo[1,2-a]piperazine ring system [WO 2009158394].

Where R² or substituents on the ring formed by R² and R⁴ containreactive functional groups such as double or triple bonds, hydroxygroups, amines and carboxylic acids, these groups may be manipulated bymethods known in the art such as oxidation, reduction, alkylation,halogenation and the like. For example, double bonds may be reduced toalkyl groups or oxidized, for example, with meta-chloro-peroxybenzoicacid (MCPBA) to provide an epoxide. Triple bonds may be reducedstereoselectively to give double bonds with a desired cis or transstereochemistry. Hydroxy groups may be oxidized to ketones, aldehydes orcarboxylic acids.

Similar reactions may be performed using commercially availablediazepines such as R- orS-hexahydro-4-[(4-methylphenysulfonyl]-2-oxo-1H-1,4-diazepine-5-carboxylicacid methyl ester,2-Cbz-8-Boc-decahydropyrazino[1,2-g][1,4]diazepine-7-carboxylic acid and2-Cbz-decahydropyrazino [1,2-g][1,4]diazepine-7-carboxylic acid.

Methods of the Invention

In one aspect of the present invention, there is provided a method oftreating or preventing the symptoms of a neuropathic condition in asubject comprising administering a compound of formula (I) or apharmaceutically acceptable salt thereof.

The compounds of formula (I) are effective in the prevention orattenuation of the symptoms of neuropathic conditions including primaryand secondary neuropathic conditions. In accordance with the presentinvention, the compounds of formula (I) can act to treat, prevent orattenuate one or more symptoms associated with neuropathic conditionsincluding, but not limited to, hyperesthesia, hyperalgesia, allodyniaand/or spontaneous burning pain. In some embodiments, the compound offormula (I) is used to prevent or attenuate one or more symptomsassociated with peripheral neuropathic conditions, illustrative examplesof which include numbness, weakness, burning pain, shooting pain, andloss of reflexes. The pain may be severe and disabling. In someembodiments, the symptom, which is the subject of the prevention and/orattenuation, is neuropathic pain. Accordingly, in a related aspect, theinvention provides methods for preventing and/or attenuating neuropathicpain in an individual, comprising administering to the individual apain-preventing or -attenuating effective amount of an AT₂ receptorantagonist, which is suitably in the form of a pharmaceuticalcomposition.

There are many possible causes of neuropathy and neuropathic pain and itwill be understood that the present invention contemplates the treatmentor prevention of symptoms of any neuropathic condition regardless of thecause. In some embodiments, the neuropathic conditions are a result ofdiseases of the nerves (primary neuropathy) and neuropathy that iscaused by systemic disease (secondary neuropathy) such as but notlimited to: diabetic neuropathy; Herpes Zoster (shingles)-relatedneuropathy; uremia-associated neuropathy; amyloidosis neuropathy; HIVsensory neuropathies; hereditary motor and sensory neuropathies (HMSN);hereditary sensory neuropathies (HSNs); hereditary sensory and autonomicneuropathies; hereditary neuropathies with ulcero-mutilation;nitrofurantoin neuropathy; tomaculous neuropathy; neuropathy caused bynutritional deficiency, neuropathy caused by kidney failure and complexregional pain syndrome. Other causes include repetitive activities suchas typing or working on an assembly line, medications known to causeperipheral neuropathy such as several antiretroviral drugs (ddC(zalcitabine) and ddI (didanosine), antibiotics (metronidazole, anantibiotic used for Crohn's disease, isoniazid used for tuberculosis),gold compounds (used for rheumatoid arthritis), some chemotherapy drugs(such as vincristine and others) and many others. Chemical compounds arealso known to cause peripheral neuropathy including alcohol, lead,arsenic, mercury and organophosphate pesticides. Some peripheralneuropathies are associated with infectious processes (such asGuillian-Barre syndrome). In certain embodiments, the neuropathiccondition is a peripheral neuropathic condition, which is suitably painsecondary to mechanical nerve injury or painful diabetic neuropathy(PDN) or related condition.

The neuropathic condition may be acute or chronic and, in thisconnection, it will be understood by persons of skill in the art thatthe time course of a neuropathy will vary, based on its underlyingcause. With trauma, the onset of symptoms may be acute, or sudden;however, the most severe symptoms may develop over time and persist foryears. Inflammatory and some metabolic neuropathies have a subacutecourse extending over days to weeks. A chronic course over weeks tomonths usually indicates a toxic or metabolic neuropathy. A chronic,slowly progressive neuropathy over many years such as occurs withpainful diabetic neuropathy or with most hereditary neuropathies or witha condition termed chronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP). Neuropathic conditions with symptoms thatrelapse and remit include the Guillian-Barre syndrome.

In another aspect of the invention there is provided a method oftreating or preventing a condition characterized by neuronalhypersensitivity in a subject comprising administering a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the condition characterized by neuronalhypersensitivity is a hyperalgesic condition such as fibromyalgia. Inother embodiments, the condition is irritable bowel syndrome which ischaracterized by neuronal hypersensitivity in the gut.

In another aspect of the invention there is provided a method oftreating or preventing a disorder associated with aberrant nerveregeneration comprising administering a compound of formula (I) or apharmaceutically acceptable salt thereof.

In some embodiments, the disorder associated with aberrant nerveregeneration also includes neuronal hypersensitivity. Examples ofdisorders associated with aberrant nerve regeneration are breast pain,interstitial cystitis and vulvodynia. In other embodiments, the disorderis a cancer chemotherapy-induced neuropathy.

In another aspect of the invention, there is provided a method oftreating or preventing inflammatory pain in a subject comprisingadministering a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Pain related to inflammation may be acute or chronic and can be due to anumber of conditions that are characterized by inflammation including,without limitation, burns such as chemical, frictional or chemicalburns, autoimmune diseases such as rheumatoid arthritis andosteoarthritis, inflammatory bowel disease such as Crohn's disease andcolitis, and other inflammatory diseases such as inflammatory boweldisease, carditis, dermatitis, myositis, neuritis and collagen vasculardiseases.

In a further aspect, the present invention provides a method of treatingor preventing impaired nerve conduction velocity in a subject comprisingadministering a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Impaired neuronal conduction velocity is a symptom of nerve dysfunctionor damage and may be present as a symptom of a large number of diseasesor disorders, particularly diseases or disorders that exhibitparesthesia as a symptom. In some embodiments, the impaired nerveconduction velocity is associated with a neuropathic condition asdescribed above. In other embodiments, the impaired nerve conductionvelocity is associated with Carpel Tunnel Syndrome, ulnar neuropathy,Guillian-Barré Syndrome, fascioscapulohumeral muscular dystrophy andspinal disc herneation.

Nerve conduction velocity is assessed by evaluating the electricalconduction of motor and sensory nerves in, the body. Motor nerveconduction velocity is measured by stimulation of a peripheral nerve andmeasuring the time taken for the electrical impulse to be detected inthe muscle associated with the nerve. The time taken is measured inmilliseconds and is converted to a velocity (m/s) by taking into accountthe distance traveled. Sensory nerve conduction, is assessed in asimilar manner with stimulation of a peripheral nerve and recording at asensory site such as a finger or paw pad.

In yet a further aspect of the invention there is provided a method ofproducing analgesia in a subject comprising administering a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is a subject having a neuropathiccondition, an inflammatory condition, impaired nerve conductionvelocity, a condition characterized by neuronal hypersensitivity or adisorder associated with aberrant nerve regeneration. In otherembodiments, the subject is a subject at risk of developing neuropathicpain, inflammatory pain, pain related to impaired nerve conductionvelocity, a condition characterized by neuronal hypersensitivity or adisorder associated with aberrant nerve regeneration.

In still another aspect of the invention there is provided a method oftreating or preventing a cell proliferative disorder in a subjectcomprising administering a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the cell proliferative disorder is a cancer,especially where the cancer is selected from leukaemia, melanoma,prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma,squamous cell carcinoma, sarquoides, fibrosarcoma, colon cancer, lungcancer and other solid tumour cancers.

In other embodiments, the cell proliferative disorder is a non-cancerousproliferative disorder. Examples of such non-cancerous proliferativedisorders include dermatological disorders such as warts, keloids,psoriasis, proud flesh disorder and also the reduction in scar tissueand cosmetic remodelling.

In a further aspect the present invention provides a method of treatingor preventing a disorder associated with an imbalance between boneresorption and bone formation in a subject comprising administering acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder associated with an imbalance betweenbone resorption and bone formation is osteoporosis.

The subjects, individuals or patients to be treated are mammaliansubjects including but not limited to humans, primates, livestockanimals such as sheep, cattle, pigs, horses, donkeys and goats;laboratory test animals such as mice, rats, rabbits and guinea pigs;companion animals such as cats and dogs or captive wild animals such asthose kept in zoos. In a particular embodiment, the subject is a human.

An “effective amount” means an amount necessary at least partly toattain the desired response, or to delay the onset or inhibitprogression or halt altogether, the onset or progression of a particularcondition being treated. The amount varies depending upon the health andphysical condition of the individual to be treated, the taxonomic groupof individual to be treated, the degree of protection desired, theformulation of the composition, the assessment of the medical situation,and other relevant factors. It is expected that the amount will fall ina relatively broad range that can be determined through routine trials.An effective amount in relation to a human patient, for example, may liein the range of about 0.1 ng per kg of body weight to 1 g per kg of bodyweight per dosage. The dosage is preferably in the range of 1 μg to 1 gper kg of body weight per dosage, such as is in the range of 1 mg to 1 gper kg of body weight per dosage. In one embodiment, the dosage is inthe range of 1 mg to 500 mg per kg of body weight per dosage. In anotherembodiment, the dosage is in the range of 1 mg to 250 mg per kg of bodyweight per dosage. In yet another embodiment, the dosage is in the rangeof 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mgper kg of body weight per dosage. In yet another embodiment, the dosageis in the range of 1 μg to 1 mg per kg of body weight per dosage. Dosageregimes may be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily, weekly,monthly or other suitable time intervals, or the dose may beproportionally reduced as indicated by the exigencies of, the situation.

Reference herein to “treatment” and “prevention” is to be considered inits broadest context. The term “treatment” does not necessarily implythat a subject is treated until total recovery. “Treatment” may alsoreduce the severity of an existing condition. The term “prevention” doesnot necessarily mean that the subject will not eventually contract adisease condition. The term “prevention” may be considered to includedelaying the onset of a particular condition. Accordingly, treatment andprevention include amelioration of the symptoms of a particularcondition or preventing or otherwise reducing the risk of developing aparticular condition.

In some embodiments, the compounds of formula (I) or theirpharmaceutically acceptable salts thereof may be administered togetherwith another therapy. Administration may be in a single composition orin separate compositions simultaneously or sequentially such that bothcompounds or therapies are active at the same time in the body.

In some embodiments, the compounds of formula (I) or theirpharmaceutically acceptable salts are administered together with anothertherapy to treat neuropathic or inflammatory pain or the underlyingcondition that is causing the neuropathic or inflammatory pain oranother therapy to treat conditions characterized by neuronalhypersensitivity, disorders associated with aberrant nerve regeneration,proliferative disorders or disorders associated with an imbalancebetween bone resorption and bone formation. In some embodiments, theamount of the second drug may be reduced when administration is togetherwith a compound of formula (I) or a pharmaceutically acceptable saltthereof.

Suitable additional drugs to treat pain include opiates such asmorphine, codeine, dihydrocodeine, hydrocodone, acetyldihydrocodeine,oxycodone, oxymorphone and buprenorphine, and non-steroidalanti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen,acetaminophen, diflunisal, salsalate, phenacetin, fenoprofen,ketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, sulindac,etodolac, ketorolac, diclofenac, nabumetone, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib,parecoxib, lumaricoxib, etoricoxib, firocoxib, rimesulide andlicofelone.

Examples of drugs to treat neuropathies include duloxetine, pregabalin,gabapentin, phenyloin, carbamazebine, levocarnitine, tricyclicantidepressants such as amitryptiline and sodium channel blockers suchas lidocaine.

Examples of chemotherapy drugs for proliferative disorders includecisplatin, carboplatin, camptothecin, carmustine, cyclophosphamide,dactinomycin, daunorubicin, dexamethasone, docetaxel, doxorubicin,etoposide, epirubicin, everolimus, gemcitibine, goserelin, trastuzumab(Herceptin®), idarubicin, interferon-alfa, irinotecan, methotrexate,mitomycin, oxaliplatin, paclitaxel, raloxifene, streptozocin, tamoxifen,topotecan, vinblastine, vincristine, abiraterone, fluorouracil,denosumab, imatinib, geftinib, lapatinib, pazopanib, rituximab,sunitinib, erlotinib and vorinistat.

Examples of drugs to treat disorders associated with an imbalancebetween bone formation and bone resorption include bisphosphonates suchas sodium alendronate, risedronate and ibandronate, raloxifene,calcitonin, teriparatide, strontium ranelate or calcium supplements.

Examples of drugs used to treat conditions characterized by neuronalhypersensitivity, such as irritable bowel syndrome, include 5HT₃receptor antagonists such as alosetron (Lotronex®).

The AT₂ receptor antagonists of the invention are also useful incombination with radiotherapy in cancer patients.

COMPOSITIONS OF THE INVENTION

While it is possible that, for use in therapy, a compound of theinvention may be administered as a neat chemical, it is preferable topresent the active ingredient as a pharmaceutical composition.

Thus, in a further aspect of the invention, there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable carrier.

The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The compounds of the invention, together with a conventional adjuvant,carrier, excipient, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to twohundred (200) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms. The compounds of the present inventioncan be administered in a wide variety of oral and parenteral dosageforms. It will be obvious to those skilled in the art that the followingdosage forms may comprise, as the active component, either a compound ofthe invention or a pharmaceutically acceptable salt or derivative of thecompound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump. To improve nasal delivery andretention the compounds according to the invention may be encapsulatedwith cyclodextrins, or formulated with their agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 1 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The pharmaceutical compositions may comprise further active ingredientssuch as other therapies to treat neuropathic or inflammatory pain or theunderlying condition that is causing the neuropathic or inflammatorypain or therapies to treat conditions characterized by neuronalhypersensitivity, disorders associated with aberrant nerve regeneration,proliferative disorders or disorders associated with an imbalancebetween bone resorption and bone formation.

The invention will now be described with reference to the followingExamples which illustrate some preferred aspects of the presentinvention. However, it is to be understood that the particularity of thefollowing description of the invention is not to supersede thegenerality of the preceding description of the invention.

EXAMPLES Abbreviations

DCM dichloromethane DBAD dibenzyl azodicarboxylate RT room temperaturePE petroleum ether EA or EtOAc ethyl acetate THF tetrahydrofuran Et₂Odiethyl ether MeOH methanol Et₃N triethylamine DMAP4-dimethylaminopyridine DIPEA N,N-disopropylethylamine Bn benzyl Bzbenzoyl TLC thin layer chromatography DABCO1,4-diazabicylco[2.2.2]octane DMF dimethylformamide LR Lawesson'sReagent TFA trifluoroacetic acid EDCI1-ethy1-3-(3-dimethylaminopropyl)carbodiimide Py Pyridine EtOH ethanolBoc t-butyloxycarbonyl IPA isopropylalcohol

General Methods Used in the Synthesis Examples

LC-MS (Agilent):

-   -   1. LC: Agilent Technologies 1200 series, Binary Pump, Diode        Array Detector. Ultimate AQ-C18, 3 μm, 2.1×50 mm column. Mobile        phase: B (MeOH) and A (0.07% HCOOH aqueous solution). Flow Rate:        0.4 mL/min at 25° C. Detector: 214 nm, 254 nm. Gradient stop        time, 5 min. Timetable:

T (min) B (%) A (%) 0 10 90 0.2 10 90 1.2 95 5 2.8 95 5 3 10 90 5 10 90

-   -   2. MS: G6110A, Quadrupole LCMS, Ion Source: ES-API, TIC: 50˜900        m/z, Fragmentor: 60, Drying gas flow: 10 L/min, Nebulizer        pressure: 35 psi, Drying gas temperature: 350° C., Vcap: 3500V.    -   3. Sample preparation: samples were dissolved in methanol at        1˜10 μg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

LC-MS (Waters):

-   -   1. LC: Waters 2695, Quaternary Pump, Waters 2996 Photodiode        Array Detector. Xbridge-C18, 3.5 μm, 2.1×50 mm column. Mobile        Phase: B (MeOH) and A (0.07% HCOOH aqueous solution). Flow Rate:        0.3 mL/min at 30° C. Detector: 214 nm, 254 nm. Gradient stop        time, 10 min. Timetable:

T (min) B (%) A (%) 0 10 90 2.5 75 25 5.0 95 5 7.5 95 5 7.6 10 90 10 1090

-   -   2. MS: Micromass QZ, TIC: 100˜900 m/z, Ion Source: ES,        Capillary: 3 kV, Cone: 3V, Extractor: 3V, Drying gas flow: 600        L/hr, cone: 50 L/hr, Desolvation temperature: 300° C., Source        temperature: 100° C.    -   3. Sample preparation: samples were dissolved in methanol at        1˜10 μg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

LC-MS (Agilent, P-2) (Positive Ion Mode) or LC-MS (Agilent, N-2)(Negative Ion Mode):

-   -   1. LC: Agilent Technologies 1200 series, Binary Pump, Diode        Array Detector. Xbridge-C18, 2.5 μm, 2.1×30 mm column. Mobile        phase: B (MeOH) and A (0.07% HCOOH aqueous solution). Flow Rate:        0.5 mL/min at 30° C. Detector: 214 nm, 254 nm. Gradient stop        time, 5 min. Timetable:

T (min) B (%) A (%) 0 80 20 0.2 80 20 0.8 5 95 2.8 5 95 3 80 20 5 80 20

-   -   2. MS: G6110A, Quadrupole LCMS, Ion Source: ES-API, TIC: 50˜900        m/z, Fragmentor: 60, Drying gas flow: 10 L/min, Nebulizer        pressure: 35 psi, Drying gas temperature: 350° C., Vcap: 3500V.    -   1. Sample preparation: samples were dissolved in methanol at        1˜10 μg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

LC-MS (Agilent, P-1) (Positive Ion Mode) or LC-MS (Agilent, N-1)(Negative Ion Mode) (Low Polarity Samples):

-   -   1. LC: Agilent Technologies 1200 series, Binary Pump, Diode        Array Detector. Xbridge-C18, 2.5 μm, 2.1×30 mm column. Mobile        phase: B (MeOH) and A (0.07% HCOOH aqueous solution). Flow Rate:        0.4 mL/min at 30° C. Detector: 214 nm, 254 nm. Gradient stop        time, 6 min. Timetable:

T (min) B (%) A (%) 0 80 20 0.2 80 20 0.8 5 95 3.8 5 95 4 80 20 6 80 20

-   -   2. MS: G6110A, Quadrupole LCMS, Ion Source: ES-API, TIC: 50˜900        m/z, Fragmentor: 60, Drying gas flow: 10 L/min, Nebulizer        pressure: 35 psi, Drying gas temperature: 350° C., Vcap: 3500V.    -   3. Sample preparation: samples were dissolved in methanol at        1˜10 μg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

Analytical HPLC:

-   -   1. (Referred to as “Aligent”) Agilent Technologies 1200 series,        Quaternary Pump, Diode Array Detector. Ultimate AQ-C18, 5 μM,        4.6×250 mm column. Mobile Phase: B (MeOH) and A (0.07% TFA        aqueous solution). Flow Rate: 1.00 mL/min at 30° C. Detector:        214 nm, 254 nm. Gradient stop time: 20 min. Timetable:

T (min) B (%) A (%) 0 40 60 3 40 60 5 60 40 7 80 20 8 95 5 15 95 5 17 4060 20 40 60

-   -   2. Sample preparation: samples were dissolved in methanol at 1        mg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

Referred to as “JULY-L” or “SYN-001”

-   -   1. Agilent Technologies 1200 series, Quaternary Pump, Diode        Array Detector. Waters Nova-pak C18, 4 μm, 3.9×150 mm column.        Mobile Phase: C (MeOH) and D (0.07% TFA aqueous solution). Flow        Rate: 1.00 mL/min at 30° C. Detector: 214 nm, 254 nm. Gradient        stop time: 15 min. Timetables:

Method name: SYN-001 (high polarity) T (min) C (%) D (%) 0 5 95 2 5 95 512 88 6 40 60 7 95 5 10 95 5 12 60 40 13 5 95 15 5 95

Method name: JULY-L (average and low polarity) T (min) C (%) D (%) 0 2080 2 20 80 4 40 60 5 70 30 6 95 5 10 95 5 11 70 20 12 20 80 15 20 80

-   -   2. Sample preparation: samples were dissolved in methanol at ˜1        mg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

Referred to as “ZSJ-2”

-   -   1. Agilent Technologies 1200 series, Quaternary Pump, Diode        Array Detector. Waters Nova-pak C18, 4 μm, 3.9×150 mm column.        Mobile Phase: C (MeOH) and D (0.07% TFA aqueous solution). Flow        Rate: 1.00 mL/min at 30° C. Detector: 214 nm, 254 nm. Gradient        stop time: 30 min. Timetable:

Method name: ZSJ-2 T (min) C (%) D (%) 0 20 80 28 95 5 30 70 30

-   -   2. Sample preparation: samples were dissolved in methanol at ˜1        mg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

Example 1 Compound 4(S)-1-(2,2-diphenylacetyl)-4-phenylpiperazine-2-carboxylic acid

1. Procedure for the Preparation of 4b

To a stirred solution of compound 4a (100 mg, 0.41 mmol) and PhB(OH)₂(75 mg, 0.61 mmol) in DCM (2 mL) was added Cu(OAc)₂ (22 mg, 0.12 mmol)at RT and the mixture was stirred overnight, TLC (MeOH:DCM=1:10) showedmost of starting material was consumed. The reaction was repeated on alarger batch of compound 4a (1.0 g, 4.1 mmol) and the reaction mixtureswere combined and washed with cold water (20 mL) then brine (10 mL×2),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography (EA:PE=1:50) to give 4b (450 mg, 31%) as acolorless oil. LC-MS (Agilent): R_(t) 3.35 min; m/z calculated forC₁₇H₂₄N₂O₄ [M+H]⁺ 321.2, [M+Na]⁺343.2. found [M+H]⁺321.1, [M+Na]⁺343.1.

2. Procedure for the Preparation of 4c

To a stirred solution of 4b (0.45 g, 1.4 mmol) in DCM (5 mL) was addedCF₃COOH (0.96 g, 8.4 mmol) at RT and the mixture was stirred at RTovernight, TLC (MeOH:DCM=10:1) showed the starting material wasconsumed. The mixture was concentrated in vacuo, the residue wasdissolved in EA (5 mL), washed with a saturated aqueous NaHCO₃ solution,brine (3 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo togive 4c (280 mg, 90%) as a colorless oil. LC-MS (Agilent): R_(t) 2.57min; m/z calculated for C₁₂H₁₇N₂O₂ [M+H]⁺ 221.1. found [M+H]⁺ 221.1.

3. Procedure for the Preparation of 4d

To a stirred solution of 4c (260 mg, 1.18 mmol) and Et₃N (238 mg, 2.36mmol) in DCM (5 mL) was added diphenylacetyl chloride (408 mg, 1.77mmol), prepared from diphenylacetic acid and thionyl chloride, at 0° C.and the mixture was stirred at RT for 10 min, TLC (MeOH:DCM=1:10) showedthe starting material was consumed. DCM/water (5 mL 10 mL) was added,the organic layer was separated, washed with brine (5 mL×2), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography (PE:EA=20:1 to 10:1) to give 4d (350 mg, 71%) as anoff-white solid. LC-MS (Agilent): R_(t) 3.30 min; m/z calculated forC₂₆H₂₇N₂O₃ [M+H]⁺ 415.2, [M+Na]⁺ 437.2. found [M+H]⁺415.2, [M+Na]⁺437.2.

4. Procedure for the Preparation of 4

To a stirred solution of 4d (350 mg, 0.84 mmol) in THF (7 mL) was addeda solution of LiOH.H₂O (53 mg, 1.27 mmol) in water (3 mL) at 0° C. andthe mixture was stirred at RT overnight, TLC (MeOH:DCM=1:10) showed thestarting material was consumed. The mixture was concentrated in vacuo toremove most of the THF. The residue was partitioned between EA (3 mL)and water (10 mL) and the mixture acidified to pH 3-4 with 1M HCl. Theorganic phase was washed with brine (5 mL×2), dried over Na₂SO₄,filtered and concentrated in vacuo. Crude 4 was washed with n-hexane togive pure 4 (280 mg, 82%) as an off-white solid. LC-MS (Agilent): R_(t)3.25 min; m/z calculated for C₂₅H₂₄N₂O₃ [M+H]⁺ 401.2, [M+Na]⁺423.2.found [M+H]⁺ 401.2, [M+Na]⁺423.2. HPLC (214 and 254 nm): R_(t) 13.53min.

Example 2 Compound 5(S)-4-benzyl-1-(2,2-diphenylacetyl)piperazine-2-carboxylic acid

1. Procedure for the Preparation of Compound 5a

To a solution of 4a (0.5 g, 2.0 mmol) in DMF (10 mL) at 0° C. was addedDIPEA (317.4 mg, 2.45 mmol) and benzyl bromide (359.1 mg, 2.1 mmol) andthe mixture was stirred at RT for 40 min, TLC (PE:EA=4:1) showed thatthe starting material was consumed. Water (30 mL) was added and themixture was extracted with EA (30 mL). The organic extract was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give 5a (650mg, 97%) as a yellow oil. LC-MS (Agilent): R_(t) 3.28 min; m/zcalculated for C₁₈H₂₆N₂O₄ [M+H]⁺ 335.1. found [M+H]⁺ 355.1.

2. Procedure for the Preparation of Compound 5b

To a solution of 5a (650 mg, 1.95 mmol) in DCM (8 mL) was added TFA(1.34 g, 11.7 mmol) and the mixture was stirred at RT overnight, TLC(PE:EA=4:1) showed that the starting material was consumed. The solventwas removed in vacuo, water (15 mL) and Et₂O (15 mL) were added and theorganic layer was separated. The aqueous phase was adjusted to pH 8 witha saturated aqueous Na₂CO₃ solution and extracted with DCM (15 mL×2).The combined organic extracts were washed with brine, dried over Na₂SO₄and concentrated in vacuo to give 5b (300 mg, 65%) as a yellow oil.LC-MS (Agilent): R_(t) 0.77 min; m/z calculated for C₁₃H₁₈N₂O₂ [M+H]⁺235.1. found [M+H]⁺235.1.

3. Procedure for the Preparation of Compound 5c

To a solution of compound 5b (300 mg, 1.28 mmol) in DCM (6 mL) was addedEt₃N (194 mg, 1.92 mmol) and a solution of diphenylacetyl chloride (354mg, 1.54 mmol) in DCM (2 mL) and the mixture was stirred at RT for 30min, TLC showed that the starting material was consumed. Water (10 mL)was added, the layers were separated and the aqueous phase was extractedwith DCM (10 mL). The combined organic extracts were washed with brine,dried over Na₂SO₄ and concentrated in vacuo. Purification by silicacolumn (PE:EA=1:0 to 3:1) gave 5c (470 mg 85%) as a white solid. LC-MS(Agilent): R_(t) 3.30 min; m/z calculated for C₂₇H₂₈N₂O₃ [M+H]⁺ 429.2.found [M+H]⁺ 429.2.

4. Procedure for the Preparation of 5

To a solution of compound 5c (250 mg, 0.58 mmol) in THF/water (6 mL/2mL) was added LiOH (73.5 mg, 1.75 mmol) and the mixture was stirred atRT overnight, TLC showed that the starting material was consumed. Mostof the THF was removed in vacuo, water (20 mL) and Et₂O (10 mL) wereadded and the Et₂O phase was removed. DCM (10 mL) was added and theaqueous layer was adjusted to pH 2-3 with a 1 M aqueous HCl solution.The layers were separated and the aqueous layer was extracted with DCM(2×10 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄ and concentrated in vacuo to give 5 (220 mg, 91%) as a whitesolid. LC-MS (Agilent): R_(t) 3.30 min; m/z calculated for C₂₆H₂₆N₂O₃[M+H]+415.2. found [M+H]⁺ 415.2. HPLC (214 and 254 nm): R_(t) 14.18 min.

Example 3 Compound 6(S)-4-(1,5-diphenyl-1H-pyrazol-3-yl)-1-(2,2-diphenylacetyl)-piperazine-2-carboxylicacid

1. Procedure for the Preparation of 6b

A mixture of the 4a (2.00 g, 13.8 mmol) and 6a (9.34 g, 41.6 mmol)(prepared according to the procedure in Tetrahedron, 2010, 66, 2843) intoluene (40 mL) was heated at 130° C. in a sealed tube for 3 hours, TLC(DCM:MeOH=20:1) showed the starting material was consumed. The solventwas removed in vacuo and the residue was purified by Al₂O₃ column(PE:EA=10:1 to 4:1) to give 6b (600 mg, 16%) as a thick yellow oil.LC-MS (Agilent): R_(t) 3.27 min; m/z calculated for C₂₁H₂₈N₂O₅S [M+H]⁺421.2, [M+Na]⁺443.2. found [M+H]⁺421.2, [M+Na]⁺443.2.

2. Procedure for the Preparation of Compound 6c

A mixture of 6b (600 mg, 1.42 mmol), DABCO (192 mg, 1.71 mmol) andPhNHNH₂ (185 mg, 1.71 mmol) in t-BuOH (30 mL) was heated at refluxovernight, TLC (PE:EtOAc=2:1) showed most of the starting material wasconsumed. The mixture was cooled to RT and concentrated in vacuo. Theresidue was dissolved in EA (30 mL) and washed with a 0.1 M aqueous HClsolution (20 mL×2) and brine, then dried over Na₂SO₄ and concentrated invacuo. Purification by chromatography (PE:EA=50:1 to 20:1) gave 6c (200mg, 30%) as a yellow solid. LC-MS (Agilent): R₁ 3.44 min; m/z calculatedfor C₂₆H₃₀N₄O₄ [M+H]⁺ 463.2, [M+Na]⁺485.2, [M+H]⁺ 463.2, [M+Na]⁺485.2.

3. Procedure for the Preparation of Compound 6d

A solution of 6c (200 mg, 0.43 mmol) in 4 M HCl/EtOH (5 mL) Was stirredat RT for 3 hours, TLC (PE:EA=4:1) showed the reaction was complete. Themixture was concentrated in vacuo and the residue was partitionedbetween DCM (20 mL) and water (20 mL). The aqueous layer was basified topH 7-8 with a saturated aqueous Na₂CO₃ solution and the layers wereseparated. The aqueous layer was extracted with DCM (20 mL) and thecombined organic extracts were washed with brine (20 mL×1), dried overNa₂SO₄ and filtered. To the filtrate was added Et₃N (53 mg, 0.52 mmol)and diphenylacetyl chloride (109 mg, 0.47 mmol) and the mixture wasstirred at RT overnight, TLC (DCM:MeOH=20:1) showed the reaction wascomplete. The mixture was washed with brine (8 mL×2), dried over Na₂SO₄,filtered and concentrated in vacuo and the residue was purified bychromatography (PE:EA=50:1 to 4:1) to give 6d (140 mg, 58%) as a whitesolid. LC-MS (Agilent): R_(t) 3.50 min; m/z calculated for C₃₅H₃₂N₄O₃[M+H]⁺ 557.3. found [M+H]⁺ 557.3.

4. Procedure for the Preparation of 6

To a mixture of 6d (130 mg, 0.23 mmol) in THF (5 mL) and H₂O (1 mL) wasadded LiOH.H₂O (24 mg, 0.58 mmol) and the mixture was stirred at RTovernight, TLC (PE:EA=4:1) showed the starting material was consumed.Most of the THF was removed in vacuo and the residue was dissolved inwater (30 mL) and washed with PE (20 mL). The aqueous layer wasacidified to pH 2-3 with a 3 M aqueous HCl solution and the resultingprecipitate was collected by filtration. The solid was dissolved in DCM,washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto give 120 mg of a solid, which was re-crystallized from EA/PE to give6 (80 mg, 64%) as a white solid. LC-MS (Agilent): R_(t) 3.52 min; m/zcalculated for C₃₄H₃₀N₄O₃ [M+H]⁺ 543.2. found [M+H]⁺ 543.2. HPLC (214and 254 nm): R_(±)8.55 min.

Example 4 Compound 7(S)-1-(2,2-diphenylacetyl)-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine-2-carboxylicacid

1. Procedure for the Preparation of Compound 7a

A mixture of compound 4a (600 mg, 2.5 mmol) and tert-butyl acetoacetate(427 mg, 2.7 mmol) in toluene (10 mL) was heated at 100° C. overnight,TLC (PE:EA=1:1) showed that most of the starting material was consumed.The mixture was cooled to RT, concentrated in vacuo and the residue waspurified by flash chromatography (PE:EA=10:1 to 4:1) to give 7a (770 mg,95%) as a yellow oil. LC-MS (Agilent): R_(t) 3.19 min; m/z calculatedfor C₁₅H₂₄N₂O₆ [M+H]⁺ 329.2, [M+Na]⁺351.2, [M+H−t-Bu]⁺272.2. found[M+H]⁺ 329.2, [M+Na]⁺351.2, [M+H−t-Bu]⁺272.2.

2. Procedure for the Preparation of Compound 7b

A mixture of 7a (600 mg, 1.8 mmol), PhNHNH₂ (217 mg, 2.0 mmol) andLawesson's reagent (808 mg, 2.0 mmol) in THF/pyridine (10 mL/1 mL) wasstirred at RT for 30 min and then heated at 55° C. for 4 h, TLC(PE:EA=1:1) showed that the starting material was consumed. The reactionwas cooled to RT and partitioned between EA (20 mL) and water (20 mL).The organic layer was separated, washed with a 1 M aqueous HCl solution,brine and dried over Na₂SO₄, then filtered and concentrated in vacuo.The residue was purified by chromatography (PE:EA=10:1 to 4:1) to give7b (400 mg, 54%) as a yellow oil. LC-MS (Agilent): R_(t) 3.47 min; m/zcalculated for C₂₁H₂₈N₄O₄ [M+H]⁺ 401.2. found [M+H]⁺ 401.2.

3. Procedure for the Preparation of Compound 7c

A mixture of compound 7b (400 mg, 1.0 mmol)) in a 4 M HCl/EtOH solution(10 mL) was stirred at RT for 4 h, TLC (PE:EA=1:1) showed the startingmaterial was consumed. The mixture was concentrated in vacuo and theresidue was partitioned between DCM (10 mL) and water (10 mL) and theaqueous layer was basified to pH 8-9 with a saturated aqueous NaHCO₃solution. The organic layer was separated and the aqueous layer wasextracted with DCM (10 mL). The combined organic extracts were washedwith brine (10 mL×2), dried over Na₂SO₄, filtered and concentrated invacuo to give the deprotected amine (250 mg) as a colorless oil, whichwas used in the next step without further purification. LC-MS (Waters):R_(t) 4.16 min; m/z calculated for C₁₆H₂₀N₄O₂ [M+H]⁺ 301.2,[M+Na]⁺323.1. found [M+H]⁺ 301.2, [M+Na]⁺323.2.

4. Procedure for the Preparation of Compound 7d

The 7c (250 mg) was dissolved in DCM (15 mL) and diphenyl acetic acid(195 mg, 0.92 mmol) was added followed by EDCI.HCl (238 mg, 1.24 mmol)and DMAP (cat). The mixture was then stirred at RT overnight, TLC(PE:EA=2:1) showed the reaction was complete. The mixture was dilutedwith DCM (15 mL) and washed with brine (20 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (PE:EA=1:0 to 10:1) to give 7d(250 mg, 50% for two steps) as a white solid. LC-MS (Agilent): R_(t)3.40 min; m/z calculated for C₃₀H₃₀N₄O₃ [M+H]⁺ 495.2, [M+Na]⁺517.2.found [M+H]⁺ 495.3, [M+Na]⁺517.3.

5. Procedure for the Preparation of Compound 7

To a solution of 7d (250 mg, 0.51 mmol) in THF/H₂O (5 mL/1 mL) was addedLiOH.H₂O (53 mg, 1.26 mmol) and the mixture was stirred at RT overnight,TLC (PE:EA=1:2) showed the reaction was complete. The mixture wasconcentrated in vacuo and the residue was dissolved in water (30 mL) andwashed with Et₂O (20 mL). The aqueous layer was cooled in an ice-waterbath and acidified to pH 4-5 with a 1 M aqueous HCl solution. Theresulting white precipitate was collected by filtration, washed withwater (15 mL×2) and dried at 50° C. overnight to give 7 (190 mg, 78%) asa white solid. LC-MS (Agilent): R_(t) 3.43 min; m/z calculated forC₂₉H₂₈N₄O₃ [M+H]⁺ 481.2. found [M+H]⁺ 481.2. HPLC (214 and 254 nm):R_(t) 8.15 min.

Example 5 Compound 8(S)-1-(2,2-diphenylacetyl)-4-phenethylpiperazine-2-carboxylic acid

1. Procedure for the Preparation of 8a

To a stirred solution of 4a (500 mg, 2.05 mmol) in DMF (10 mL) was addedDIPEA (310 mg, 2.4 mmol) and 2-bromoethyl benzene (359 mg. 2.1 mmol) andthe mixture was heated at 70° C. overnight, TLC (PE:EA=1:1) showed thestarting material was consumed. Water (15 mL) was added and the mixturewas extracted with EA (10 mL×2). The combined organic extracts werewashed with brine (10 mL×2), dried over Na₂SO₄ and concentrated in vacuoto give crude 8a (1.0 g) as a colorless oil, which was used directly inthe next step. LC-MS (Agilent): R_(t) 3.32 min; m/z calculated forC₂₉H₂₈N₂O₄ [M+H]⁺ 349.2. found [M+H]⁺ 349.2.

2. Procedure for the Preparation of Compound 8b

To a stirred solution of 8a (700 mg, 1.93 mmol) in DCM (10 mL) was addedTFA (1.32 g, 11.58 mmol) and the mixture was stirred at RT for 5 h, TLC(PE:EA=1:1) showed the starting material was consumed. The mixture wasconcentrated in vacuo and the residue was diluted with water (10 mL) andwashed with Et₂O (5 mL×2). The aqueous layer was basified to pH 9-10with a saturated aqueous Na₂CO₃ solution and extracted with DCM (10mL×2). The combined organic extracts were washed with brine (10 mL×2),dried over Na₂SO₄ and concentrated in vacuo to give 8b (300 mg) as acolorless oil, which was used directly in next step.

3. Procedure for the Preparation of 8c

To a stirred solution of 8b (300 mg, 1.2 mmol) in DCM (5 mL) at 0° C.was added Et₃N (243 mg, 2.4 mmol) and diphenylacetyl chloride (331 mg,1.44 mol) and the mixture was then stirred at RT for 1 h, TLC(DCM:MeOH=20:1) showed the starting material was consumed. DCM (5 mL)and water (5 mL) were added, the organic layer was separated, washedwith brine (10 mL×2), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by chromatography (DCM:MeOH=1:0 to 20:1) to give 8c(300 mg, 62%) as a colorless oil. LC-MS (Agilent): R_(E) 3.38 min; m/zcalculated for C₂₈H₃₀N₂O₃ [M+Na]⁺ 465.2. found [M+Na]⁺465.2.

4. Procedure for the Preparation of 8

To a stirred solution of 8c (300 mg, 0.67 mmol) in THF (7 mL) at 0° C.was added a solution of LiOH.H₂O (42 mg, 1.0 mmol) in water (3 mL) andthe mixture was stirred at RT overnight, TLC (PE:EA=1:1) showed thestarting material was consumed. Most of the THF was removed in vacuo andthe resulting aqueous solution was washed with ether (5 mL×2). EA (5 mL)was added and the aqueous layer was acidified to pH 2˜3 with a 1 Maqueous HCl solution. The organic layer was collected and washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to givecrude 8, which was washed with hexane to give pure 8 (90 mg, 31%) as awhite solid. LC-MS (Agilent): R_(t) 3.13 min; m/z calculated forC₂₇H₂₈N₂O₃ [M+H]⁺ 429.2. found [M+H]⁺ 429.2. HPLC (214 and 254 nm):R_(t) 11.49 min.

Example 6 Compound 9(S)-4-cinnamyl-1-(2,2-diphenylacetyl)piperazine-2-carboxylic acid

1. Procedure for the Preparation of 9a

To a stirred solution of compound 4a (500 mg, 2.05 mmol) in DMF (8 mL)at 0° C. was added DIPEA (318 mg, 2.46 mmol) and trans-cinnamyl bromide(444 mg, 2.25 mmol) and the mixture was stirred at RT for 5 h, TLC(PE:EA=2:1) showed that the starting material was consumed. Water (30mL) was added and the mixture was extracted with EA (20 mL×2). Thelayers were separated and the combined organic extracts were washed withwater, brine and dried, over Na₂SO₄. The solvent was removed in vacuo togive crude 9a (0.8 g) as a yellow oil, which was used directly in thenext step. LC-MS (Agilent): R_(t) 3.11 min; m/z calculated forC₂₀H₂₈N₂O₄ [M+H]⁺ 361.2. found [M+H]⁺ 361.2.

2. Procedure for the Preparation of Compound 9b

To a solution of compound 9a (0.8 g, 2.2 mmol) in DCM (10 mL) was addedTFA (1.5 g, 13.3 mmol) and the mixture was stirred at RT overnight, TLCshowed that the starting material was consumed. The mixture wasconcentrated in vacuo and the residue was dissolved in water (20 mL) andwashed with Et₂O (15 mL). DCM (15 mL) was added and the aqueous layerwas basified to pH 7-8 with a saturated aqueous Na₂CO₃ solution. Theorganic layer was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give 9b (600 mg, 100%) as yellowoil. LC-MS (Agilent): R_(t) 2.78 min; m/z calculated for C₁₅H₂₀N₂O₂[M+H]⁺ 261.1. found [M+H]⁺ 261.1.

3. Procedure for the Preparation of 9c

To a solution of 9b (600 mg, 2.3 mmol) in DCM (15 mL) at 0° C. was addedEt₃N (354 mg, 3.5 mmol) and diphenylacetyl chloride (650.0 mg, 2.8 mmol)and the mixture was stirred at RT for 10 min, TLC (PE:EA=2:1) showedthat the starting material was consumed. Water (20 mL) was added, thelayers were separated and the organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by silicacolumn (PE:EA=10:1 to 4:1) gave 9c (700 mg, 70%) as a white solid. LC-MS(Agilent): R_(t) 3.17 min; m/z calculated for C₂₉H₃₀N₂O₃ [M+H]⁺ 455.2.found [M+H]⁺ 455.2.

4. Procedure for the Preparation of 9

To a stirred mixture of 9c (700 mg, 1.5 mmol) in THF/water (10 mL/3 mL)was added LiOH.H₂O (194 mg, 4.5 mmol) and the mixture was stirred at RTovernight, TLC showed that the starting material was consumed. Most ofthe THF was removed in vacuo and the residue was dissolved in water (20mL) and washed with Et₂O (15 mL). DCM (15 mL) was added and the aqueouslayer was acidified to pH 2-3 with a 1 M aqueous HCl solution. Theorganic layer was separated and washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. Recrystallization from EA/PE gave 9(500 mg, 75%) as a white solid. LC-MS (Agilent): R_(t) 3.18 min; m/zcalculated for C₂₈H₂₈N₂O₃ [M+H]⁺ 441.2. found [M+H]⁺ 441.2. HPLC (214and 254 nm): R_(t) 11.87 min.

Example 7 Compound 10(S)-1-(2,2-diphenylacetyl)-4-(3-phenylpropyl)piperazine-2-carboxylicacid

To a solution of compound 9 (300 mg, 0.68 mmol) in EA (10 mL) was added10% Pd/C (30 mg) and the mixture was stirred at RT under a N₂ atmosphere(1 atm pressure) overnight, LCMS analysis showed that the startingmaterial was consumed. The catalyst was removed by filtration throughCelite and the filtrate was concentrated in vacuo. Purification bysilica column (DCM:MeOH=1:0 to 20:1) gave 10 (100 mg, 33%) as a whitesolid. LC-MS (Agilent): R_(t) 3.15 min; m/z calculated for C₂₈H₃₀N₂O₃[M+H]⁺ 443.2. found [M+H]⁺ 443.2. HPLC (214 and 254 nm): R_(t) 11.72min.

Example 8 Compound 16(S)-4-(1-benzyl-3-methyl-1H-pyrazol-5-yl)-1-(2,2-diphenylacetyl)piperazine-2-carboxylicacid

1. Procedure for the Preparation of Compound 16a

To a solution of 7a (400 mg, 1.2 mmol) in toluene (10 mL) was addedLawesson's reagent (747 mg, 0.6 mmol) and the mixture was heated at 75°C. overnight, TLC (DCM:MeOH=20:1) showed the starting material wasconsumed. The mixture was concentrated in vacuo and the residue waspurified by silica column (PE:EA=10:1 to 4:1) to give 16a (120 mg, 29%)as a yellow oil. LC-MS (Agilent): R_(t) 3.33 min; m/z calculated forC₁₅H₂₄H₂O₅ [M+Na]⁺367.1. found [M+Na]⁺367.1.

2. Procedure for the Preparation of 16b

To a solution of 16a (120 mg, 0.35 mmol) in toluene (10 mL) was addedBnNHNH₂.2HCl (81.6 mg, 0.42 mmol). Two drops of pyridine were added andthe mixture was heated at 90° C. overnight, TLC (PE:EA=2:1) showed thestarting material was consumed. The mixture was concentrated in vacuoand the residue was purified by silica column (PE:EA=10:1 to 4:1) togive 16b (100 mg, 69%) as a yellow oil. LC-MS (Agilent): R_(t) 3.66 min;m/z calculated for C₂₂H₃₀N₄O₄ [M+H]⁺ 415.2, [M+Na]⁺437.3, [M+H]⁺ 415.2,[M+Na]⁺437.2.

3. Procedure for the Preparation of 16c

A mixture of 16b (100 mg, 0.24 mmol) in a 4 M HCl/EtOH solution (5 mL)was stirred at RT for 3 h, TLC (PE:EA=2:1) showed that most of thestarting material was consumed. Most of the ethanol was removed in vacuoand the residue was diluted with water (10 mL) and washed with Et₂O (10mL). The aqueous layer was basified to pH 7-8 with a saturated aqueousNa₂CO₃ solution and extracted with DCM (10 mL×2). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to give 16c (75 mg, 100%) as a yellow oil. LC-MS(Agilent): R_(t) 3.33 min; m/z calculated for C₁₇H₂₂N₄O₂ [M+H]⁺ 315.2,[M+Na]⁺337.2, [M+H]⁺ 315.2, [M+Na]+337.1.

4. Procedure for the Preparation of Compound 16d

To a solution of 16c (70.0 mg, 0.22 mmol) and diphenyl acetic acid (52.0mg, 0.25 mmol) in DCM (5 mL) was added EDCI.HCl (85.5 mg, 0.44 mmol) andDMAP (5 mol %) and the mixture was stirred at RT overnight, TLC(PE:EA=2:1) showed that the starting material was consumed. The mixturewas diluted with DCM and washed with saturated NaHCO₃ solution, brine,dried over Na₂SO₄ and concentrated in vacuo. Purification by silicacolumn (PE: EA=10:1 to 5:1) gave 16d (95 mg, 86%) as a yellow solid.LC-MS (Agilent): R_(t) 3.53 min; m/z calculated for C₃₁H₃₂N₄O₃ [M+H]⁺509.2, [M+Na]⁺531.3, [M+H]⁺ 509.2, [M+Na]⁺531.2.

5. Procedure for the Preparation of 16

To a mixture of 16d (90.0 mg, 0.18 mmol) in THF/water (6 mL/2 mL) wasadded LiOH.H₂O (22.3 mg, 0.53 mmol) and the mixture was stirred at RTovernight, TLC showed that the starting material was consumed. Most ofthe THF was removed in vacuo and the residue was dissolved in water (20mL) and washed with Et₂O (15 mL). The aqueous layer was acidified to pH3 with a 1 M aqueous HCl solution and the resulting precipitate wascollected by filtration and dried to give 16 (55 mg, 63%) as a whitesolid. LC-MS (Agilent): R_(t) 3.48 min; m/z calculated for C₃₀H₃₀N₄O₃[M+H]⁺ 495.2. found [M+H]⁺ 495.2. HPLC (JULY-L) (214 and 254 nm): R_(t)8.21 min.

Example 9 Compound 17(S)-4-(1-benzyl-5-methyl-1H-pyrazol-3-yl)-1-(2,2-diphenylacetyl)piperidine-2-carboxylicacid

1. Procedure for the Preparation of 17a

To a solution of 16a (450 mg, 1.3 mmol) in toluene (10 mL) was addedN₂HNH₂H₂O (85% solution in water, 197 mg, 3.4 mmol) and the mixture washeated at 70° C. overnight, TLC (DCM:MeOH=20:1) showed that the startingmaterial was consumed. The mixture was concentrated in vacuo and theresidue was purified by column chromatography (DCM:MeOH=100:1 to 50:1)to give 17a (350 mg, 83%) as a yellow solid. LC-MS (Agilent): R_(t) 3.64min; m/z calculated for C₁₅H₂₄H₄O₄ [M+H]⁺ 325.2. found [M+H]⁺ 325.2.

2. Procedure for the Preparation of 17b

A mixture of 17a (320 mg, 0.99 mmol), benzyl bromide (186 mg, 1.09 mmol)and Cs₂CO₃ (387 mg, 1.2 mmol) in DMF (8 mL) was heated at 45° C.overnight, TLC (DCM:MeOH=20:1) showed that most of the starting materialwas consumed. The mixture was cooled to RT, poured into ice-water (30mL) and extracted with EA (20 mL×2). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. Purification by column chromatography (DCM:MeOH=1:0 to 20:1) gave17b (300 mg, 73%) as a yellow oil and recovered starting material (60mg, 19%). LC-MS (Agilent): R_(t) 3.93 min; m/z calculated for C₂₂H₃₀N₄O₄[M+H]⁺ 415.2. found, [M+H]⁺ 415.2.

3. Procedure for the Preparation of 17c

A mixture of 17b (300 mg, 0.72 mmol) in a 4 M HCl/MeOH solution wasstirred at RT for 3 h, TLC showed that the starting material wasconsumed. The mixture was concentrated in vacuo and the residue waspartitioned between DCM (20 mL) and a saturated aqueous NaHCO₃ solution(30 mL). The layers were separated and the aqueous layer was furtherextracted with DCM (20 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo togive crude 17c (240 mg, >100%) as a yellow oil, which was used directlyin the next step. LC-MS (Agilent): R_(t) 3.32 min; m/z calculated forC₁₇H₂₂N₄O₂ [M+H]⁺ 315.2, [M+Na]⁺337.2. found, [M+H]⁺ 315.2,[M+Na]⁺337.2.

4. Procedure for the Preparation of 17d

To a solution of 17c (240 mg, 0.76 mmol) and diphenyl acetic acid (195mg, 0.92 mmol) in DCM (10 mL) was added EDCI.HCl (190 mg, 0.99 mmol) andthe mixture was stirred at RT overnight, TLC (DCM:MeOH=10:1) showed thatthe starting material was consumed. The mixture was washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (DCM:MeOH=1:0 to 20:1) togive 17d (320 mg, 82%) as thick colorless oil. LC-MS (Agilent): R_(t)3.98 min; m/z calculated for C₃H₃₂N₄O₃ [M+H]⁺ 509.3, [M+Na]⁺531.3,[M+H]⁺ 509.3, [M+Na]⁺531.2.

5. Procedure for the Preparation of 17

To a mixture of 17d (160 mg, 0.31 mmol) in THF/water (10 mL/1.5 mL) wasadded LiOH.H₂O (40 mg, 0.94 mmol) and the mixture was stirred at RTovernight, LCMS analysis showed that the starting material was consumed.Most of the THF was removed in vacuo and the residue was dissolved inwater (10 mL), acidified to pH 4-5 with a 3 M aqueous HCl solution andextracted with DCM (15 mL×2). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo togive 17 and 16 in a 4:1 ratio (150 mg, 98%), as a white solid. Ratiodetermined by integration of the ¹14 NMR spectrum. LC-MS (Agilent):R_(t) 4.01 min; m/z calculated for C₃₀H₃₀N₄O₃ [M+H]⁺ 495.2. found [M+H]⁺495.3. HPLC (214 and 254 nm): R_(t) 9.21 min.

Example 10 Compound 23(S)-4-(1-benzyl-3-(-trifluoromethyl)-1H-pyrazol-5-yl)-1-(2,2-diphenylacetyl)piperazine-2-carboxylicacid

1. Procedure for the Preparation of 23a

A mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (4.72 g, 25.6 mmol),benzyl-hydrazine dihydrochloride (5.00 g, 25.63 mmol) and TsOH.H₂O (490mg, 2.56 mmol) in EtOH (30 mL) was heated at reflux overnight, TLC(PE:EA=2:1) showed that the starting material was consumed. The mixturewas concentrated in vacuo and the residue was partitioned between EA (15mL) and water (15 mL). The organic layer was separated, washed withbrine (10 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was re-crystallised from Et₂O to give 23a (2.22 g, 36%) as awhite solid. LC-MS (Agilent): R_(t) 3.75 min; m/z calculated forC₁₁H₉F₃N₂O [M+H]⁺ 243.1, [M+Na]⁺265.1. found [M+H]⁺ 243.1, [M+Na]⁺265.1.

2. Procedure for the Preparation of 23b

To a mixture of 23a (2.22 g, 9.17 mmol) and DMF (2.68 g, 36.7 mol) wasadded POCl₃ (10 mL) dropwise at 0° C. The mixture was then heated at 80°C. under a N₂ atmosphere for 5 h, TLC (PE:EA=2:1) showed that thestarting material was consumed. The mixture was allowed to cool to RT,poured into ice-water (150 mL) and extracted with EA (50 mL). To theorganic layer was added water (40 mL) and the aqueous layer was adjustedto pH 7 with K₂CO₃. The organic layer was collected, washed with brine(40 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (PE:EA=1:0 to 10:1) to give 23b(1.78 g, 67%) as a thick yellow oil. LC-MS (Agilent): R_(t) 4.08 min;m/z calculated for C₁₂H₈ClF₃N₂O [M+H]⁺ 289.0. [M+Na]⁺311.0. found [M+H]⁺289.0. [M+Na]⁺311.0.

3. Procedure for the Preparation of 23c

A mixture of 23b (1.78 g, 6.16 mmol), 4a (1.81 g, 7.40 mmol) and CsF(6.55 g, 43.2 mmol) in DMF (30 mL) was heated at 80° C. under a N₂atmosphere overnight, TLC (PE:EA=10:1) showed that the starting materialwas consumed. The mixture was allowed to cool to RT, poured into icewater (250 mL) and extracted with EA (80 mL×2). The combined organicextracts were washed with brine (100 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by chromatography(PE:EA=25:1 to 10:1) to give 23c (1.29 g, 42%) as a red solid. LC-MS(Agilent): R_(t) 4.43 min; m/z calculated for C₂₃H₂₇F₃N₄O₅[M-Boc+H]⁺397.1. [M+Na]⁺519.2. found [M-Boc+H]⁺ 397.1. [M+Na]⁺519.2.

4. Procedure for the Preparation of 23d

To a solution of 23c (1.29 g, 2.60 mmol) in acetone (30 mL) at 0° C. wasadded Jones reagent (7.0 mL, 5.2 mmol) dropwise and the mixture wasstirred at 0° C. for 2 h, TLC (PE:EA=4:1) showed that most of thestarting material was consumed. The reaction was quenched withisopropanol (3 mL), stirred for 5 min then filtered to remove theprecipitate and the filtrate was concentrated in vacuo. The residue wasdissolved in water (20 mL), basified to pH 8 with Et₃N and extractedwith DCM (15 mL×2). The combined organic extracts were washed with brine(30 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (PE:EA=10:1 to 4:1) to give 23d(450 mg, 34%) as a white solid. LC-MS (Agilent): R_(t) 4.25 min; m/zcalculated for C₂₃H₂₇F₃N₄O₆ [M-Boc+H]⁺413.1, [M+H]⁺ 513.2, [M+Na]⁺535.2.found [M-Boc+H]⁺ 413.1, [M+H]⁺ 513.2, [M+Na]⁺535.2.

5. Procedure for the Preparation of 23e

23d (380 mg, 0.74 mmol) was heated at 180° C. under a N₂ atmosphere for2 h, TLC (PE:EA=2:1) showed that the starting material was consumed,then cooled to RT to give 23e (300 mg) as grey oil, which was useddirectly in the next step. LC-MS (Agilent): R_(t) 3.96 min; m/zcalculated for C₂₂H₂₇F₃N₄O₄ [M+H]⁺ 469.2, [M+Na]⁺491.2. found [M+H]⁺469.2, [M+Na]⁺491.2.

6. Procedure for the Preparation of 231

To a solution of 23e (300 mg) in MeOH (5 mL) was added a 4 M HCl/MeOHsolution (25 mL) and the mixture was stirred at RT overnight, TLC(DCM:MeOH=10:1) showed that the starting material was consumed. Themixture was concentrated in vacuo and the residue was dissolved in water(20 mL) and washed with Et₂O. The aqueous phase was basified to pH 7˜8with K₂CO₃ and extracted with EA (15 mL×2). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (PE:EA=7:1 to 1:1) to give 23f(100 mg, 42%) as a colorless oil. LC-MS (Agilent): R_(t) 3.76 min; m/zcalculated for C₁₇H₁₉F₃N₄O₂ [M+H]⁺ 369.2, [M+Na]⁺391.2. found [M+H]⁺369.2, [M+Na]⁺391.2.

7. Procedure for the Preparation of 231

To solution of 23f (90 mg, 0.24 mmol) and Et₃N (32 mg, 0.32 mmol) in DCM(20 mL) at 0° C. was added diphenylacetyl chloride (68 mg, 0.29 mmol)and the mixture was stirred at RT overnight, TLC (PE:EA=4:1) showed thata major new product was formed. The mixture was washed with brine (15mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (PE:EA=10:1 to 5:1) to give 23 g(100 mg, 73%) as a white solid. LC-MS (Agilent): R₁ 4.01 min; m/zcalculated for C₃₁H₂₉F₃N₄O₃ [M+H]⁺ 563.3, [M+Na]⁺585.2. found [M+H]⁺563.3, [M+Na]⁺585.2.

8. Procedure for the Preparation of 23

A mixture of 23 g (100 mg, 0.18 mmol) and LiOH.H₂O (23 mg, 0.53 mmol) inTHF/water (8 mL/2 mL) was stirred at RT overnight, TLC (DCM:MeOH=10:1)showed the starting material was consumed. Most of the THF was removedin vacuo and the residue was dissolved in water (10 mL) and acidified topH 4˜5 with a 3 M aqueous HCl solution. The resulting precipitate wascollected by filtration and dried at 60° C. to give 23 (78 mg, 80%) as awhite solid. LC-MS (Agilent): R_(t) 4.51 min; m/z calculated forC₃₀H₂₇N₄O₃ [M+H]⁺ 549.2, [M+Na]⁺571.2. found [M+H]⁺ 499.2, [M+Na]⁺571.2.HPLC (JULY-L) (214 and 254 nm)): R_(t) 9.27 min.

Example 11 Compound 24(5)-1-(2,2-diphenylacetyl)-4-(3-phenylprop-2-yn-1-yl)piperazine-2-carboxylicacid

1. Procedure for the Preparation of 24b

To a solution of 4a (150 mg, 0.61 mmol) in DMF (5 mL) was added K₂CO₃(102 mg, 0.74 mmol) and 24a (144 mg, 0.74 mmol) and the mixture washeated at 70° C. overnight, TLC (DCM:MeOH=10:1) showed that the startingmaterial was consumed. The mixture was poured into ice-water (20 mL) andextracted with EA (15 mL×2). The combined organic extracts were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by chromatography (PE:EA=10:1 to 8:1) togive 24b (70 mg, 31%) as a colorless oil. LC-MS (Agilent, P-2): R_(t)3.19 min; m/z calculated for C₂₀H₂₆N₂O₄ [M+H]⁺ 359.2, [M+Na]⁺381.2.found [M+H]⁺ 359.2, [M+Na]⁺381.2.

2. Procedure for the Preparation of 24c

A mixture of 24b (70 mg, 0.20 mmol) and a 4 M HCl/MeOH solution (5 mL)was stirred at RT overnight, TLC (PE:EA=2:1) showed that the startingmaterial was consumed. The mixture was concentrated in vacuo, theresidue was dissolved in water (10 mL), basified to pH 9 with K₂CO₃ andextracted with DCM (10 mL×2). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated in vacuo. The residue wasdissolved in DCM (5 mL), diphenyl acetic acid (45 mg, 0.22 mmol) andEDCI (45 mg, 0.23 mmol) were added and the mixture was stirred at RTovernight, TLC (DCM:MeOH-10:1) showed that the starting material wasconsumed. The mixture was washed with water (5 mL), brine (5 mL×2),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography (PE:EA=10:1 to 4:1) to give 24c (37 mg, 42%)as a colorless oil. LC-MS (Agilent, P-2): R_(t) 3.10 min; m/z calculatedfor C₂₉H₂₈N₂O₃ [M+H]⁺ 453.2. found [M+H]⁺ 453.2.

3. Procedure for the Preparation of 24

A mixture of 24c (37 mg, 0.081 mmol) and LiOH.H₂O (10 mg, 0.245 mmol) inTHF/H₂O (2 mL 0.5 mL) was stirred at RT overnight, TLC (PE:EA=2:1)showed the starting material was consumed. The mixture was concentratedin vacuo, the residue was dissolved in water (2 mL), acidified to pH 4˜5with a 4 M aqueous HCl solution and extracted with DCM (5 mL×2). Thecombined organic extracts were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bypreparative HPLC to give 24 (15 mg, 41%) as a white solid. LC-MS(Agilent, P-2): R_(t) 3.10 min; m/z calculated for C₂₈H₂₆N₂O₃ [M+H]⁺439.2. found [M+H]⁺ 439.2. HPLC (JULY-L) (214 and 254 nm): R_(t) 9.04min.

Example 12 Compound 25(S)-1-(2,2-diphenylacetyl)-4-(3-fluorophenylprop-2-yn-1-yl)piperazine-2-carboxylicacid

1. Procedure for the Preparation of 25a

To a solution of 4a (200 mg, 0.82 mmol) in DMF (5 mL) was added K₂CO₃(170 mg, 1.23 mmol) and 25a (170 mg, 0.81 mmol) and the mixture wasstirred at 30° C. overnight, TLC (PE:EA=2:1) showed that the startingmaterial was consumed. The mixture was partitioned between. EA (20 mL)and H₂O (20 mL), the organic layer was separated, washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography (PE:EA=10:1 to 2:1) to give 25b (100 mg, 32%)as a brown oil. LC-MS (Agilent, P-2): R_(t) 3.277 min; m/z calculatedfor C₂₀H₂₅FN₂O₄ [M+H]⁺ 377.2, [M+Na]⁺ 399.2. found [M+H]⁺ 377.2,[M+Na]⁺399.2.

2. Procedure for the Preparation of 25c

A mixture of 25b (100 mg, 0.27 mmol) and a 4 M HCl/MeOH solution (5 mL)was stirred at RT overnight, TLC (PE:EA=2:1) showed that the startingmaterial was consumed. The mixture was concentrated in vacuo, theresidue was dissolved in water, basified to pH 9-10 with K₂CO₃ andextracted with DCM (20 mL×3). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated. The residue was dissolved in DCM(5 mL), TEA (42 mg, 0.41 mmol) and 2,2-diphenylacetyl chloride (74 mg,0.32 mmol) were added at 0° C. and the mixture was allowed to warm to RTand stirred for 10 min, TLC (DCM:MeOH=10:1) showed that the startingmaterial was consumed. The reaction was quenched with water and theorganic layer was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography (PE:EA=10:1 to 1:1) to give 25c (100 mg, 77%) as a yellowoil. LC-MS (Agilent, P-2): R_(t) 3.449 min; m/z calculated forC₂₉H₂₇FN₂O₃ [M+H]⁺ 471.2. found [M+H]⁺ 471.2.

3. Procedure for the Preparation of 25

A mixture of 25c (100 mg, 0.21 mmol) and LiOH.H₂O (36 mg, 0.85 mmol) inTHF/H₂O (3 mL/1 mL) was stirred at RT overnight, TLC (PE:EA=1:2) showedthat the starting material was consumed. The mixture was concentrated invacuo, the residue was dissolved in water (5 mL) and acidified to pH 3˜4with a 3 M aqueous HCl solution. The resulting precipitate was collectedby filtration and dried to give 25 (66 mg, 69%) as a white solid. LC-MS(Agilent, P-2): R_(t) 3.206 min; m/z calculated for C₂₈H₂₅FN₂O₃ [M+H]⁺457.2. found [M+H]⁺ 457.2. HPLC (JULY-L) (214 and 254 nm): R_(t) 9.071min.

Example 13 Compound 26(S)-1-(2,2-diphenylacetyl)-4-(4-phenylbut-3-yn-1-yl)piperazine-2-carboxylicacid

1. Procedure for the Preparation of 26a

A mixture of 4a (500 mg, 2.05 mmol), K₂CO₃ (339 mg, 2.46 mmol) and4-bromo-1-butyne (273 mg, 2.05 mmol) in DMF (5 mL) was heated at 60° C.overnight. More 4-bromo-1-butyne (273 mg, 2.05 mmol) was added andheating was continued at 60° C. for 6 h, TLC (DCM:MeOH=10:1) showed thestarting material was consumed. The mixture was poured into ice-water(30 mL) and extracted with EA (10 mL×2), the combined organic extractswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography(PE:EA=1:0 to 9:1) to give 26a (367 mg, 60%) as a colorless oil. LC-MS(Agilent, P-2): R_(t) 2.85 min; m/z calculated for C₁₅H₂₄N₂O₄ [M+H]⁺296.2, [M+Na]⁺319.2. found [M+H]⁺ 296.2, [M+Na]⁺319.2.

2. Procedure for the Preparation of 26b

A mixture of 26a (367 mg, 1.24 mmol) in 4 M HCl/MeOH (10 mL) was stirredat RT overnight, TLC (PE:EA=4:1) showed that the starting material wasconsumed. The mixture was concentrated in vacuo, the residue wasdissolved in water (10 mL), basified to pH 9˜10 with K₂CO₃ and extractedwith IPA/CHCl₃ (1/3 v/v, 8 mL×7). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue wasdissolved in DCM (10 mL) and cooled to 0° C. Et₃N (205 mg, 1.49 mmol)was added followed by the slow addition of diphenyl acetyl chloride (343mg, 1.49 mmol). The mixture was stirred at RT for 10 min, TLC(DCM:MeOH=10:1) showed that the starting material was consumed. Themixture was washed with water (10 mL), brine (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography (PE:EA=10:1 to 5.5:1) to give 26b (331 mg, 68%) ascolorless oil. LC-MS (Agilent, P-2): R_(t) 3.07 min; m/z calculated forC₂₄H₂₆N₂O₃ [M+H]⁺ 391.2, [M+Na]⁺ 413.2. found [M+H]⁺ 391.2,[M+Na]⁺413.2.

3. Procedure for the Preparation of 26c

A mixture of 26b (50 mg, 0.13 mmol), iodobenzene (31 mg, 0.15 mmol), CuI(2 mg, 0.006 mmol), Pd(PPh₃)Cl₂ (9 mg, 0.013 mmol) and Et₃N (39 mg, 0.39mmol) in THF (5 mL) was heated at 90° C. under microwave irradiation for30 min, TLC (PE:EA=2:1) showed that the starting material was consumed.The reaction was repeated (50 mg of 26b was used) and the two reactionmixtures were combined and partitioned between EA/brine (20 mL/20 mL).The organic layer was collected, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography(PE:EA=1:0 to 4:1) to give 26c (60 mg, 50%) as colorless oil. LC-MS(Agilent, P-2): R_(t) 3.26 min; m/z calculated for C₃₀H₃₀N₂O₃ [M+H]⁺467.2. found [M+H]⁺ 467.3.

4. Procedure for the Preparation of 26

A mixture of 26c (60 mg, 0.12 mmol) and LiOH.H₂O (19 mg, 0.45 mmol) inTHF/H₂O (3 mL/1 mL) was stirred at RT overnight, TLC (PE:EA=2:1) showedthat the starting material was consumed. The mixture was concentrated invacuo, the residue was dissolved in water (10 mL), acidified to pH 4˜5with a 4 M HCl aqueous solution and extracted with DCM (10 mL×2). Thecombined organic extracts were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bypreparative HPLC to give 26 (55 mg, 94%) as a white solid. LC-MS(Agilent, P-2): R_(t) 3.06 min; m/z calculated for C₂₉H₂₈N₂O₃ [M+H]⁺453.2. found [M+H]⁺ 453.2. HPLC (JULY-L) (214 and 254 nm): R_(t) 9.31min.

Example 14 Compound 27(S)-1-(2,2-diphenylacetyl)-4-(4-(4-fluororophenyl)but-3-yn-1-yl)piperidine-2-carboxylicacid

1. Procedure for the Preparation of 27a

To a solution of 1-bromo-4-fluorobenzene (2.00 g, 11.0 mmol) in THF (30mL) was added but-3-yn-1-ol (0.88 g, 12 mmol), Et₃N (2.22 g, 22.0 mmol),CuI (104 mg, 0.55 mmol) and Pd(PPh₃)₂Cl₂ (700 mg, 1.1 mmol) and themixture was heated at reflux under a N₂ atmosphere overnight, TLC(PE:EA=2:1) showed a new product formed. The mixture was cooled to RT,partitioned between EA/H₂O (30 mL/40 mL) and the organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography(PE:EA=1:0 to 3:1) to give 27a (200 mg, 9%) as a white solid.

2. Procedure for the Preparation of 27b

To a solution 27a (200 mg, 1.22 mmol) and PPh₃ (319 mg, 1.22 mmol) inTHF (10 mL) at 0° C. under a N₂ atmosphere was added CBr₄ (424 mg, 1.28mmol) and the mixture was allowed to warm slowly to RT and stirred for 3h. Another batch of PPh₃ (160 mg, 0.61 mmol) and CBr₄ (212 mg, 0.64mmol) were added and stirring was continued at RT overnight, TLC(PE:EA=2:1) showed that most of the starting material was consumed. EA(2 mL) was added to the mixture followed by PE (5 mL) and the resultingprecipitate was removed by filtration. The filtrate was concentrated invacuo and the residue was purified by chromatography (100% PE) to give27b (200 mg, 72%) as a colorless oil.

3. Procedure for the Preparation of 27c

A mixture of 4a (215 mg, 0.88 mmol), 27b (200 mg, 0.88 mmol) and K₂CO₃(146 mg, 1.06 mmol) in DMF (10 mL) was heated at 60° C. overnight, TLC(PE:EA=4:1) showed that most of the starting material was consumed. Themixture was poured into ice-water (50 mL), extracted with EA (15 mL×2)and the combined organic extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography (PE:EA=1:0 to 8:1) to give 27c (13 mg, 4%) as a colorlessoil. LC-MS (Agilent, P-2): R_(t) 3.11 min; m/z calculated forC₂₁H₂₇FN₂O₄ [M+H]⁺ 391.2. Found [M+H]⁺ 391.2.

4. Procedure for the Preparation of 27d

A mixture of 27c (13 mg, 0.033 mmol) in a 4 M HCl/MeOH solution (5 mL)was stirred at RT for 30 min, TLC (PE:EA=4:1) showed that the startingmaterial was consumed. The mixture was concentrated in vacuo, DCM (10mL) was added to the residue and then concentrated again in vacuo. Theresidue was dissolved in DCM (5 mL) and the solution was basified to pH7 with Et₃N. More Et₃N (10 mg, 0.1 mmol) was added followed bydiphenylacetyl chloride (8 mg, 0.033 mmol) and the mixture was stirredat RT overnight, TLC (PE:EA=2:1) showed a major new product formed. Themixture was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography(PE:EA=6:1 to 4:1) to give 27d (11 mg, 66%) as a colorless oil. LC-MS(Agilent, P-2): R_(t) 2.87 min; m/z calculated for C₃₀H₂₉FN₂O₃ [M+H]⁺485.2. found [M+H]⁺ 485.2.

5. Procedure for the Preparation of 27

A mixture of 27d (11 mg, 0.023 mmol) and LiOH.H₂O (3 mg, 0.068 mmol) inTHF/H₂O (3 mL/1 mL) was stirred at RT overnight, then stirred at 27° C.for 5 h, TLC (PE:EA=2:1) showed that the starting material was consumed.The mixture was concentrated in vacuo to remove the THF and the residuewas dissolved in water (10 mL), acidified to pH 4˜5 with a 4 M aqueousHCl solution and extracted with DCM (10 mL×3). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC togive 27 (7 mg, 66%) as a white solid. LC-MS (Agilent, P-2): R_(t) 2.55min; m/z calculated for C₂₉H₂₇FN₂O₃ [M+H]⁺ 471.2. found [M+H]⁺471.2.HPLC (JULY-L) (214 and 254 nm): R_(t) 9.19 min.

Example 15 Compound 28(S)-4-(1-benzyl-3-methyl-1H-pyrazolyl)-N—(N,N-dimethylsulfamoyl)-1-(2,2-diphenylacetyl)piperazine-2-carboxamide

1. Procedure for the Preparation of 28b.

To a solution of 28a (400 mg, 1.18 mmol) in toluene (10 mL) was addedtert-butyl 3-oxobutanoate (187 mg, 1.18 mmol) and the mixture was heatedat 100° C. overnight, TLC (DCM:MeOH=20:1) showed that the startingmaterial was consumed. The mixture was cooled to RT and concentrated invacuo to afford 28b (445 mg, 89%) as a colorless oil, which was useddirectly in the next step. LC-MS (Agilent, P-2): R_(t) 2.592 min; m/zcalculated for C₂₄H₂₆N₂O₅ [M+H]⁺ 423.2, [M+Na]⁺445.2. found [M+H]⁺423.2, [M+Na]⁺ 445.2.

2. Procedure for the Preparation of 28c

To a stirred solution of 28b (445 mg, 1.05 mmol) in toluene (5 mL) wasadded Lawesson's reagent (213 mg, 0.527 mmol) and the mixture was heatedat 75° C. overnight, TLC (PE:EA=1:2) showing that the starting materialwas consumed. The mixture was concentrated in vacuo and the residue waspurified by chromatography (PE:EA=5:1 to 1:2) to give 28c (180 mg, 39%)as a pale yellow solid. LC-MS (Agilent, P-2): R_(t) 2.522 min; m/zcalculated for C₂₄H₂₆N₂O₄S [M+Na]⁺461.1. found [M+Na]⁺461.1.

3. Procedure for the Preparation of 28d

To a solution of 28c (180 mg, 0.41 mmol) in toluene (10 mL) was addedBnNHNH₂.2HCl (96 mg, 0.49 mmol) and the mixture was heated at 90° C.overnight, TLC (DCM:MeOH=50:1) showed that the starting material wasconsumed. The mixture was concentrated in vacuo and the residue waspurified by chromatography (DCM:MeOH=1:0 to 50:1) to give 28d (105 mg,50%) as a yellow solid. LC-MS (Agilent, P-2): R_(t) 2.74 min; m/zcalculated for C₃₁N₃₂N₄O₃ [M+H]⁺ 509.3, [M+Na]⁺531.3. found [M+H]⁺509.2, [M+Na]⁺531.2.

4. Procedure for the Preparation of 28e

A mixture of 28d (105 mg, 0.21 mmol) and LiOH.H₂O (34 mg, 0.84 mmol) inTHF/H₂O (3 mL/1 mL) was stirred at RT overnight, TLC (DCM:MeOH=20:1)showed that the starting material was consumed. The mixture wasconcentrated in vacuo to remove the THF, the residue was dissolved inwater (30 mL), acidified to pH 4 with a 3 M aqueous HCl solution andextracted with DCM (20 mL×2). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (DCM: MeOH=1:0 to 20:1) to give16 (75 mg, 72%) as a yellow solid. LC-MS (Agilent, P-2): R_(t) 2.80 min;m/z calculated for C₃₀H₃₀N₄O₃ [M+H]⁺ 495.2. found [M+H]⁺ 495.3.

5. Procedure for the Preparation of 28

A mixture of 16 (70 mg, 0.14 mmol), N,N-dimethylsulfamide (17 mg, 0.17mmol), DMAP (5 mg, 0.042 mmol) and DCC (35 mg, 0.17 mmol) in DCM (1 mL)was stirred at RT overnight, TLC (DCM:MeOH=10:1) showed that thestarting material was consumed. The mixture was partitioned between DCM(20 mL) and brine (20 mL) and the organic layer was separated, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography (DCM:MeOH=1:0 to 50:1) to give 28 (40 mg,47%) as a yellow solid. LC-MS (Agilent, P-2): R_(t) 2.77 min; m/zcalculated for C₃₂H₃₆N₆O₄S [M+H]⁺ 601.3. found [M+H]⁺ 601.3. HPLC(JULY-L) (214 and 254 nm): R_(t) 9.41 min.

Biological Example 1 AT₂ Receptor Binding

Media and Solutions

-   -   1. Trypsin-EDTA (for Preparation of 100 mL)        -   Trypsin 0.25 g        -   2% EDTA 2 mL        -   PBS 98 mL        -   Dissolve trypsin in 2% EDTA and PBS completely; sterilize            the solution by passing through a 0.20 μM membrane filter;            store at 4° C.    -   2. DMEM Medium (for Preparation of 1 L)        -   The powder was dissolved into 950 mL of distilled water with            gentle stirring until the solution becomes clear.        -   Add NaHCO₃ 1.176 g for DMEM medium.        -   Adjust pH of medium to 0.2-0.3 below final working pH using            1 M NaOH or 1 M HCl. Add slowly with stirring.        -   Dilute to 1 liter with ddH₂O.        -   Sterilize the medium immediately by filtration.        -   Store at 4° C.    -   3. TE Buffer        -   20 mM Tris-HCl, pH 7.4,        -   5 mM EDTA    -   4. Binding Assay Buffer        -   50 mM Hepes, pH 7.4        -   5 mM MgCl₂        -   1 mM CaCl₂        -   0.2% BSA    -   5. Wash Buffer        -   50 mM Hepes, pH 7.4

Procedures for HEK293AT₂ Receptor Transient Cell

Transfection

-   -   Cells were plated into 150 mm dish at 50% density for transient        transfection. Cells were ready for transfection after overnight        incubation (the confluence reaches around 80%).    -   75 μL Lipofectamine™2000 diluted in 6.25 mL OptiMEM I Reduced        Serum Medium, was mixed gently, and incubated at room        temperature for 5 minutes. 50 μg expression plasmid DNA diluted        in 6.25 mL OptiMEM I Reduced Serum Medium without serum was        mixed gently.    -   After the 5 minute incubation, the diluted DNA was combined with        the diluted Lipofectamine™2000 (total volume is 12.5 mL). The        mixture was mixed gently and incubated for 30 minutes at room        temperature to allow the DNA-Lipofectamine™2000 complexes to        form.    -   The 12.5 mL DNA-Lipofectamine™2000 complexes were added into the        150 mm dish and mixed gently by rocking the dish back and forth.    -   The cells were incubated at 37° C. with 5% CO₂ for 48 hours.    -   Cells were collected and stored frozen at −80° C.

Procedures for HEK293AT₂ Receptor Cell Membrane Preparation

-   -   Frozen HEK293AT₂ receptor (transient transfected) cells were        homogenized in ice cold TE buffer for 10 s.    -   The homogenate was centrifuged at 25,000 g for 30 minutes.    -   The pellet was resuspended in ice cold tissue buffer.    -   Protein concentrations were determined using Bradford assay        method with BSA as standard.    -   The membrane protein was frozen under −80° C.

Compound Preparation

Solutions of all compounds were prepared by microplate liquid handlingequipment such as Janus or Precision 2000. Compounds, dissolved in DMSOwere stored in a Freezer. Compounds were prepared from 30 mM in 100%DMSO.

Step 1: Dose Plate Preparation (96 Well Plate)

-   -   Add the 3 μL [30 mM] compound stock to column 1 on the plate.    -   Add 15 μL of 100% DMSO to column 1.    -   Add 10.81 μL of 100% DMSO to column 2-12.    -   Transfer 5 μL from column 1 into column 2 (half log dilution).    -   Transfer 5 μL from column 2 into column 3 (half log dilution).    -   Transfer 5 μL from column 3 into column 4 (half log dilution).    -   Transfer 5 μL from column 4 into column 5 (half log dilution).    -   Transfer 5 μL, from column 5 into column 6 (half log dilution).    -   Transfer 5 μL from column 6 into column 7 (half log dilution).    -   Transfer 5 μL from column 7 into column 8 (half log dilution).    -   Transfer 5 μL from column 8 into column 9 (half log dilution).    -   Transfer 5 μL from column 9 into column 10 (half log dilution)    -   Transfer 5 μL from column 10 into column 11 (half log dilution)    -   Transfer 5 μL from column 11 into column 12 (half log dilution).

All the compounds were diluted using Precision 2000 microplate liquidhandling equipment. The top concentration of compound was 5 mM with 100%DMSO.

Step 2: Working Plate Preparation (96 Well Plate)

-   -   Compounds were diluted 50-fold with buffer.    -   49 μL buffer was added to the well of 96 well plate.    -   1 μL compound solution from dose plate was transferred to the        corresponding well of working plate.    -   The top concentration of compound was 100 μM with 2% DMSO.

Step 3: Assay Plate Preparation (96 Well Plate)

15 μL of compound solution was transferred from each well of workingplate to the well of assay plate by Janus. Each compound was assayed induplicate in each plate and there were 4 compounds per plate.

Procedures for AT₂ Receptor Binding Assay

-   -   120 μL membrane (5 mg protein/well) was incubated with 15 μL of        [¹²⁵I]-CGP42112A and 15 μL of compound at RT for 1.5 hrs.    -   The binding reaction was stopped by rapid filtration through        Unifilter GF/C plates (presoaked in 0.3% (v:v) BSA).    -   Plate was washed three times with ice cold wash buffer.    -   The filtration plates were dried at 37° C. overnight.    -   50 μL of scintillation cocktail was added to each well.    -   Radioactivity was determined using MicroBetaTriluxmicroplate        scintillation counter.

Data Analysis

Data was analyzed through 4 parameter logic using Prism 5.0 software.

The results are shown in the following Table:

Compound IC₅₀ (nM) 4 408 5 383.2 6 3045 7 155 8 1267 9 4105 10 517.1 1640.26 23 93.85 24 4161 25 3923 26 1319

Biological Example 2 AT₁ Receptor Binding

Evaluation of the affinity of the test compounds for the humanangiotensin-II AT₁ receptor in transfected HEK-293 cells was determinedin a radioligand assay (Le, et al., Eur. J. Pharmacol., 2005, 513:35).

Cell membrane homogenates (8 μg protein) were incubated for 120 min at37° C. with 0.005 nM ^([125])[Sar1-Ile8]angiotensin-II in the absence orpresence of the test compound in a buffer containing 50 mM Tris-HCl (pH7.4), 5 mM MgCl₂, 1 mM EDTA and 0.1% BSA. Nonspecific binding wasdetermined in the presence of 10 mM angiotensin-II.

Following incubation, the samples were filtered rapidly under vacuumthrough glass fibre filters (GF/B, Packard) presoaked with 0.3% PEI andrinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cellharvester (Unifilter, Packard). The filters were dried then counted forradioactivity in a scintillation counter (Topcount, Packard) using ascintillation cocktail (Microscint 0, Packard). The results wereexpressed as a percent inhibition of the control radioligand specificbinding.

The standard reference compound was saralasin, which was tested in eachexperiment at several concentrations to obtain a competition curve fromwhich its IC₅₀ was calculated.

The assay was performed in a volume of 200 μL in a 96 well plate. Testcompounds used were compounds 16 and 23.

Neither compound had sufficient binding activity for the AT₁ receptor toallow an IC₅₀ to be determined. The maximum concentration of testcompound used was 10 μM.

REFERENCES

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1. A compound of formula (I):

wherein X is —CHR⁴—, —CH₂CHR⁴— or —C(═O)—; R¹ is —C(═O)CHR⁵R⁶,—C(═O)NR⁵R⁶, —C(═O)CH₂CHR⁵R⁶, —C(═O)CH═CR⁵R⁶, —C(═S)CHR⁵R⁶, —C(═S)NR⁵R⁶,—C(═S)CH₂CHR⁵R⁶, —C(═S)CH═CR⁵R⁶, —C(═NR⁷)CHR⁵R⁶, —C(═NR⁷)NR⁵R⁶,—C(═NR⁷)CH₂CHR⁵R⁶ or —C(═NR⁷)CH═CR⁵R⁶; R² is —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C(═O)R⁸, —C(═O)NHR⁷, —SO₂N(R⁷)₂, —W-cycloalkyl,—W-cycloalkenyl, —W-aryl, —W-heterocyclyl, —W-heteroaryl,—W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl, —W—Z—Y-heterocyclylor —W—Z—Y-heteroaryl; R³ is a carboxylic acid, —CH₂CO₂H, —C(═O)C(═O)OH,—C(═O)NH₂, —CH₂C(═O)NH₂, —CN, —CH₂CN, a carboxylic acid bioisostere or a—CH₂-carboxylic acid bioisotere; R⁴ is hydrogen or together with R²forms a fused cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroarylring optionally substituted with one or two substituents selected from—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —C₁₋₆alkyleneR⁹, —C₂₋₆alkenyleneR⁹,—C₂₋₆alkynyleneR⁹, —OC₀₋₆alkyleneR⁹, —OC₂₋₆alkenyleneR⁹,—OC₂₋₆alkynyleneR⁹, —C(═O)C₀₋₆alkyleneR⁹, —C(═O)C₂₋₆alkenyleneR⁹,—C(═O)C₂₋₆alkynyleneR⁹, —C(═O)OC₀₋₆alkyleneR⁹, —C(═O)OC₂₋₆alkenyleneR⁹,—C(═O)OC₂₋₆alkynyleneR⁹, —SO₂NHC₀₋₆alkyleneR⁹, —SO₂NHC₂₋₆alkenyleneR⁹,—SO₂NHC₂₋₆alkynyleneR⁹, —NHSO₂C₀₋₆alkyleneR⁹, —NHSO₂C₂₋₆alkenyleneR⁹,—NHSO₂C₂₋₆alkynyleneR⁹, —NH(═O)NHR¹⁰, —NHC(═O)OR¹⁰ or —CH(OH)CH(OH)R¹⁰;R⁵ and R⁶ are independently selected from hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl, heteroaryl, —CH₂cycloalkyl, —CH₂cycloalkenyl, —CH₂aryl,—CH₂heterocyclyl and —CH₂heteroaryl; provided that both R⁵ and R⁶ arenot hydrogen; R⁷ is hydrogen, —C₁₋₆alkyl, aryl or —C₁₋₆alkylenearyl; R⁸is —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl or —C₂₋₆alkylenearyl; R⁹is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl; R¹⁰ is—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl or heteroaryl; W is a covalent bond, —SO—, —SO₂— —C(═O)—,—C(═O)N(H)—, —C₁₋₄alkylene-, —C₂₋₄alkenylene-, —C₂₋₄alkynylene-,—C₁₋₃alkyleneQC₁₋₃alkylene-, —C₁₋₄alkyleneQ-, —C₂₋₄alkenyleneQ- or—C₂₋₄alkynyleneQ-; Z is -cycloalkyl-, -cycloalkenyl-, -aryl-,-heterocyclyl- or -heteroaryl-; Y is a covalent bond, —O—, —S—, —SO—,—SO₂— —N(R⁷)—, —C(═O)—, —N(R⁷)C(═O)—, —C(═O)N(R⁷)—, —C₁₋₃alkylene-,—C₂₋₃alkenylene-, —C₂₋₃alkynylene-, —C₁₋₃alkyleneQC₁₋₃alkylene-,-QC₁₋₄alkylene-, -QC₂₋₄alkenylene-, -QC₂₋₄alkynylene-, —C₁₋₄alkyleneQ-,—C₂₋₄alkenyleneQ-, —C₂₋₄alkynyleneQ- -QC₁₋₄alkyleneQ-,-QC₂₋₄alkenyleneQ- or -QC₂₋₄alkynyleneQ-; and Q is —O—, —S—, —SO—, —SO₂——N(R⁷)—, —C(═O)—, —N(R⁷)C(═O)— or —C(═O)N(R⁷)—; wherein each cycloalkyl,cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionallysubstituted; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 wherein X is —CH₂— or —CH₂CH₂—.
 3. Acompound according to claim 2 wherein X is —CH₂—.
 4. A compoundaccording to claim 1 wherein R¹ is —C(═O)CH(aryl)(aryl),—C(═O)CH(aryl)(cycloalkyl), —C(═O)CH(cycloalkyl)(cycloalkyl),—C(═O)N(aryl)(aryl), —C(═O)N(aryl)(cycloalkyl) or—C(═O)N(cycloalkyl)(cycloalkyl) wherein each aryl or cycloalkyl isoptionally substituted with one or more substituents selected from—C₁₋₃alkyl, —OC₁₋₃alkyl and halo.
 5. A compound according to claim 4wherein R¹ is —C(═O)CH(phenyl)(phenyl), —C(═O)CH (phenyl)(cyclohexyl),—C(═O)CH(cyclohexyl)(cyclohexyl), —C(═O)N (phenyl)(phenyl),—C(═O)N(phenyl)(cyclohexyl) or —C(═O)N(cyclohexyl)(cyclohexyl) whereineach phenyl or cyclohexyl is optionally substituted with one or moresubstituents selected from —C₁₋₃alkyl, —OC₁₋₃alkyl and halo.
 6. Acompound according to claim 1 wherein R² is —C₁₋₆alkyl, —C₂₋₆alkenylcycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl,heterocyclylaryl, —C₁₋₄alkylenecycloalkyl, —C₁₋₄ alkylenecycloalkenyl,—C₁₋₄alkylenearyl, —C₁₋₄alkyleneheterocyclyl, —C₁₋₄alkylenehetero aryl,—C₂₋₄alkenylenecycloalkyl, —C₂₋₄alkenylenecycloalkenyl,—C₂₋₄alkenylenearyl, —C₂₋₄alkenyleneheterocyclyl,—C₂₋₄alkenyleneheteroaryl, —C₂₋₄alkynylenecycloalkyl,—C₂₋₄alkynylenecycloalkenyl, —C₂₋₄alkynylenearyl,—C₂₋₄alkynyleneheterocyclyl, —C₂₋₄alkynyleneheteroaryl heterocyclylaryl,heteroarylaryl heterocyclylC₁₋₃alkylenearyl,—C₁₋₃alkyleneheterocyclylaryl, —C₁₋₃alkyleneheteroarylaryl,—CH₂C(═O)NHCH₂cycloalkyl, —CH₂C(═O)NHCH₂cycloalkenyl,—CH₂C(═O)NHCH₂aryl, —CH₂C(═O)NHCH₂heterocyclyl, —CH₂C(═O)NHCH₂heteroaryl, —C(═O)NHC₁₋₃alkylenecycloalkyl, —C(═O)NHC₁₋₃alkylenecycloalkenyl,—C(═O)NHC₁₋₃alkylenearyl, —C(═O)NHC₁₋₃alkyleneheterocyclyl,—C(═O)NHC₁₋₃alkyleneheteroaryl, —CH₂SO₂C₁₋₃alkylenecycloalkyl,—CH₂SO₂C₁₋₃alkylenecycloalkenyl, —CH₂SO₂C₁₋₃alkylenearyl,—CH₂SO₂C₁₋₃alkyleneheterocyclyl, —CH₂SO₂C₁₋₃alkyleneheteroaryl,—CH₂OC₁₋₃alkylenecycloalkyl, —CH₂OC₁₋₃alkylenecycloalkenyl,—CH₂OC₁₋₃alkylenearyl, —CH₂OC₁₋₃alkyleneheterocyclyl or—CH₂OC₁₋₃alkyleneheteroaryl; wherein each cycloalkyl, cycloalkenyl,aryl, heterocyclyl and heteroaryl is optionally substituted with one ortwo substituents.
 7. A compound according to claim 6 wherein R² isphenyl, benzyl, —CH₂CH₂phenyl, —CH₂CH═CH-phenyl, —CH₂C≡C-phenyl,—CH₂C≡C-4-fluorophenyl, —CH₂CH₂C≡C-phenyl, —CH₂CH₂C≡C-4-fluorophenyl,—CH₂CH₂CH₂phenyl 2-methylbutyl 5-(3-methyl-1-phenylpyrazole)3-(1,5-diphenylpyrazole) 3-(5-phenylpyrazole)3-(5-methyl-1-phenylpyrazole), 3-(5-(1-methylethyl)-1-phenylpyrazole2-(5-phenyloxazole) 5-(5-benzyloxazole) 5-(1-benzyl-3-methylpyrazole)3-(1-benzyl-5-methylpyrazole, —CH₂-4-(2-phenyloxazole)5-(1-benzyl)-3-trifluoromethylpyrazole and-5-(1-benzyl-3-methylpyrazole, wherein each cycloalkyl, cycloalkenyl,aryl, heterocyclyl and heteroaryl is optionally substituted.
 8. Acompound according to claim 1 wherein R³ is —CO₂H, —CH₂CO₂H, —C(═O)NH₂,—CN, —C(═O)C(═O)OH, —C(═O)NHSO₂C₁₋₆alkyl, —C(═O)NHSO₂phenyl,—C(O)NHSO₂N(CH₃)₂, —C(═O)NHSO₂CF₃—SO₃H or —PO₃H₂.
 9. A compoundaccording to claim 8 wherein R³ is —CO₂H.
 10. A compound according toclaim 1 wherein R⁴ is H.
 11. A compound according to claim 1 wherein R²and R⁴ together form a fused aryl, heterocyclyl or heteroaryl ringoptionally substituted with one or two substituents selected from -aryl,—C₁₋₃alkylenearyl Oaryl, —OC₁₋₃alkylenearyl and —C(═O)OC₁₋₃alkylenearyl.12. A compound according to claim 11 wherein R² and R⁴ together form afused heterocyclyl or heteroaryl ring optionally substituted withphenyl, benzyl Obenzyl, or —CO₂benzyl.
 13. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 14. A method of treating or preventing neuropathicpain or inflammatory pain in a subject comprising administering acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 15. A method of treating or preventing acondition characterized by neuronal hypersensitivity, impaired nerveconduction velocity, a cell proliferative disorder, a disorderassociated with an imbalance between bone resorption and bone formationor a disorder associated with aberrant nerve regeneration in a subjectcomprising administering a compound of formula (I) according to claim 1or a pharmaceutically acceptable salt thereof.
 16. (canceled) 17.(canceled)
 18. A method of producing analgesia in a subject comprisingadministering a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 19. (canceled)
 20. (canceled)21. (canceled)